JP6805172B2 - Histone deacetylase inhibitors and compositions and methods of their use - Google Patents

Description

Cross-reference to related applications This application claims interests under US Patent Act Article 119 (e) of US Patent Provisional Application No. 62 / 158,363 filed May 7, 2015, by reference in its entirety. Incorporated herein.

Specific histone deacetylase (HDAC) inhibitors, their compositions, and methods of their use are provided herein.

Histone deacetylase (HDAC) is a zinc-containing enzyme that catalyzes the removal of acetyl groups from the ε-amino terminus of lysine residues clustered near the amino terminus of nucleosome histones. There are 11 known, metal-dependent human histone deacetylases, grouped into 4 classes based on the structure of their ancillary domains. Class I includes HDAC1, HDAC2, HDAC3 and HDAC8 and has a homologous relationship with yeast RPD3. HDAC4, HDAC5, HDAC7 and HDAC9 belong to class IIa and have a homologous relationship with yeast HDAC1. HDAC6 and HDAC10 contain two catalytic sites and are classified as Class IIb, while HDAC11 has a conserved residue in its catalytic center shared by both Class I and Class II deacetylases. Sometimes placed in class IV.

Equation I

[式中、
Wは、N又はCR⁵であり;Xは、N又はCR⁶であり;Yは、N又はCR⁷であり;Zは、N又はCR⁸であり;ただし、W、X、Y、及びZのうち2つ以下は、Nであり;
R¹は、H及びC₁〜C₃アルキルから選択され;
R²は、C₁〜C₂ハロアルキル又は3若しくは4員のシクロアルキルで任意選択で置換されているC₂〜C₃アルキレンであり;
R³及びR⁴は、これらが結合している窒素原子と一緒になって、
4、5、6、若しくは7員の複素単環式基、又は
6、7、8、9、若しくは10員の複素二環式基を形成し、
それらのそれぞれは、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換され、ここでアリール及びヘテロアリールは、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換され、
ただし、R³及びR⁴が、これらが結合している窒素原子と一緒になって、5又は6員の複素単環式基を形成する場合、
i)R²は、C₁〜C₂ハロアルキル又は3若しくは4員のシクロアルキルで置換されているC₂〜C₃アルキレンである、又は
ii)R⁸は、ハロ若しくはC₁〜C₃アルキルである、又は
iii)5若しくは6員の複素単環式基は、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3若しくは4員のシクロアルコキシ、3若しくは4員のシクロアルキル、3若しくは4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で置換され、ここでアリール及びヘテロアリールは、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換され;
R⁵、R⁶、R⁷及びR⁸は、H、C₁〜C₄アルキル、C₁〜C₄ハロアルキル、及びハロからそれぞれ独立に選択される]の化合物又はその薬学的に許容される塩、光学異性体若しくは光学異性体の混合物が提供される。

[During the ceremony,
W is N or CR ⁵ ; X is N or CR ⁶ ; Y is N or CR ⁷ ; Z is N or CR ⁸ ; where W, X, Y, and Z Two or less of them are N;
R ¹ is selected from H and C _{1 to} C ₃ alkyl;
R ² is C ₂ -C ₃ alkylene which is optionally substituted with C ₁ -C ₂ haloalkyl, or 3 or 4-membered cycloalkyl;
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
4, 5, 6, or 7-membered complex monocyclic group, or
Form 6, 7, 8, 9, or 10-membered complex bicyclic groups,
Each of them is C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, It is optionally substituted with 1 to 5 substituents independently selected from 3- or 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, where the aryl and heteroaryl are C ₁ Further optionally further substituted with 1 to 5 substituents independently selected from ~ C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively.
However, if R ³ and R ⁴ combine with the nitrogen atom to which they are attached to form a 5- or 6-membered complex monocyclic group.
i) R ² is a C ₂ -C ₃ alkylene substituted with C ₁ -C ₂ haloalkyl, or 3 or 4-membered cycloalkyl, or
ii) R ⁸ is halo or C _{1 to} C ₃ alkyl, or
iii) 5- or 6-membered heteromonocyclic groups are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy. , 3 or 4 membered cycloalkyl, 3 or 4 membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, each substituted with 1-5 substituents independently selected, where aryl and Heteroaryls are optionally further substituted with 1 to 5 substituents, each independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo;
R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from H, C _{1 to} C ₄ alkyl, C _{1 to} C ₄ haloalkyl, and halo, respectively] compounds or pharmaceutically acceptable salts thereof. , Optical isomers or mixtures of optical isomers are provided.

Also provided are pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.

Also provided is a method of making a pharmaceutical composition comprising the steps of mixing the compounds described herein or pharmaceutically acceptable salts thereof, and pharmaceutically acceptable carriers.

Also, a method of treating a condition or disorder mediated by at least one histone deacetylase in a patient in need of such treatment, in which a therapeutically effective amount of a compound described herein. Alternatively, a method is provided that comprises the step of administering a pharmaceutically acceptable salt thereof.

As used herein, the following terms, sentences and symbols are generally intended to have the meanings set forth below, except to the extent that the context in which they are used is different.

A dash ("-") that is not between two letters or two symbols is used to indicate the bond point for the substituent. For example, -CONH ₂ is bonded through a carbon atom.

"Optional" or "arbitrarily" means that the event or situation subsequently described may or may not occur, and that the description is an example of an event or situation occurring, and that it does not occur. Means to include an example. For example, "optionally substituted alkyl" includes both "alkyl" and "substituted alkyl" as defined below. For those skilled in the art, with respect to any group containing one or more substituents, such groups are sterically impractical, infeasible to synthesize, and / or essentially. It will be understood that it is not intended to introduce any substitutions or substitution patterns that are unstable.

"Alkyl" includes the number of carbon atoms shown, usually straight and branched chains with 1 to 20 carbon atoms, such as 1 to 8 carbon atoms, such as 1 to 6 carbon atoms. To do. For example, C _{1 to} C ₆ alkyls include both straight and branched alkyl from 1 to 6 carbon atoms. Examples of alkyl groups are methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methyl. Examples include pentyl. An alkylene is another subset of an alkyl, which refers to the same residue as an alkyl but has two attachment points. The alkylene group will usually have 2 to 20 carbon atoms, such as 2 to 8 carbon atoms, such as 2 to 6 carbon atoms. For example, C ₀ alkylene shows a covalent bond and C ₁ alkylene is a methylene group. When an alkyl residue with a particular number of carbons is named, it is intended to include all geometric isomers with that number of carbons, so for example, "butyl" is n-butyl, sec-. Includes butyl, isobutyl and t-butyl, "propyl" means including n-propyl and isopropyl.

The term "alkylene" refers to the number of carbon atoms shown, usually 1 to 20 carbon atoms, such as 1 to 8 carbon atoms, such as 1 to 6 carbon atoms or 1 to 4 carbon atoms. Includes straight and branched dirados with. Examples of C _{1 to} C ₄ alkylene include methylene, 1,1-ethyene, 1,2-ethylene, 1,1-propylene, 1,2-propylene, 1,3-propylene, 1,1- Includes butylene, 1,2-butylene, 1,3-butylene, 1,4-butylene, 2-methyl-1,2-propylene, and 2-methyl-1,3-propylene.

"Alkoxy" refers to oxygen bridges such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyloxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy. , 3-Methylpentoxy, etc., means the indicated number of carbon atoms of the alkyl group. Alkoxy groups will typically have 1 to 6 carbon atoms bonded through an oxygen bridge.

"Aryl" refers to an aromatic carbon ring having the indicated number of carbon atoms, such as 6-12 or 6-10 carbon atoms. The aryl group may be monocyclic or polycyclic (for example, bicyclic, tricyclic). In some examples, both rings of the polycyclic aryl group are aromatic (eg, naphthyl). In another example, the polycyclic aryl group may include a non-aromatic ring (eg, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl) fused to an aromatic ring, provided that the polycyclic aryl is The groups are attached to the parent structure via atoms in the aromatic ring. Therefore, the 1,2,3,4-tetrahydronaphthalene-5-yl group (where the moiety is attached to the parent structure via an aromatic carbon atom) is considered to be an aryl group, while 1,2. , 3,4-Tetrahydronaphthalene-1-yl, which is attached to the parent structure via a non-aromatic carbon atom, is not considered an aryl group. Similarly, the 1,2,3,4-tetrahydroquinoline-8-yl group (where the moiety is attached to the parent structure via an aromatic carbon atom) is considered an aryl group, while 1 The 2,3,4-tetrahydroquinoline-1-yl group (where the moiety is attached to the parent structure via a non-aromatic nitrogen atom) is not considered an aryl group. However, the term "aryl" is used independently of the binding point (eg, both quinoline-5-yl and quinoline-2-yl are heteroaryl groups), as defined herein, "hetero". "Aryl" is not included or overlapped. In some examples, the aryl is phenyl or naphthyl. In one particular example, the aryl is phenyl.

A divalent radical formed from a substituted benzene derivative and having a free valency at a ring atom is named a substituted phenylene radical. Divalent radicals derived from monovalent polycyclic hydrocarbon radicals by removing one hydrogen atom from carbon atoms with free binding valences whose names end in "-yl" are the corresponding monovalents. Named by adding "-idene" to the name of the radical, for example, a naphthyl group with two attachment points is called naphthylden.

"Carboxy" indicates -C (O) OH.

"Cyano" means -CN.

A "cycloalkyl" is a non-aromatic, fully saturated carbon ring with the number of carbon atoms shown, eg, 3 to 10, or 3 to 8, or 3 to 6 ring carbon atoms. Shows the ring of. The cycloalkyl group may be monocyclic or polycyclic (eg, bicyclic, tricyclic). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl and cyclohexyl, as well as crosslinked spiro rings and caged ring groups (eg norbornane, bicyclo [2.2.2] octane). .. In addition, the ring of one of the polycyclic cycloalkyl groups may be aromatic, except that the polycyclic cycloalkyl group is attached to the parent structure via a non-aromatic carbon. For example, the 1,2,3,4-tetrahydronaphthalene-1-yl group (where the moiety is attached to the parent structure via a non-aromatic carbon atom) is a cycloalkyl group, while 1 , 2,3,4-Tetrahydronaphthalene-5-yl (where the moiety is attached to the parent structure via an aromatic carbon atom) is not considered a cycloalkyl group. That is, it is considered an aryl group.

The term "cycloalkoxy" means "-O-cycloalkyl", which is as defined herein.

The term "halo" includes fluoro, chloro, bromo and iodine, and the term "halogen" includes fluorine, chlorine, bromine and iodine.

The term "haloalkyl" means a C _1-6 alkyl group, where the alkyl is substituted with one halogen until fully substituted, and the fully substituted C _1-6 haloalkyl is of formula C. _n L _{2n + 1} (in the equation, L is a halogen and "n" is 1, 2, 3 or 4); if more than one halogen is present, these are It may be the same or different and is selected from the group consisting of F, Cl, Br and I, eg F. Examples of C _1-4 haloalkyl groups include, but are not limited to, fluoromethyl, difluoromethyl, trifluoromethyl, chlorodifluoromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl and the like.

The term "haloalkoxy" means a haloalkyl that is directly attached to an oxygen atom. Examples include, but are not limited to, difluoromethoxy, trifluoromethoxy, 2,2,2-trifluoroethoxy, pentafluoroethoxy and the like.

A "heteroaryl" is an indication that it is constructed of one or more heteroatoms (eg, 1, 2, 3 or 4 heteroatoms) selected from N, O and S and the atom of the remaining ring is carbon. It shows an aromatic ring containing the number of atoms (eg, 5-12 or 5-10 membered heteroaryl). Heteroaryl groups do not contain adjacent S and O atoms. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 2. In some embodiments, the total number of S and O atoms in the heteroaryl group does not exceed 1. Unless otherwise specified, heteroaryl groups may be attached to the parent structure by carbon or nitrogen atoms, as the valency allows. For example, "pyridyl" includes a 2-pyridyl group, a 3-pyridyl group and a 4-pyridyl group, and "pyrrolill" includes a 1-pyrrolill group, a 2-pyrrolill group and a 3-pyrrolill group. When nitrogen is present in the heteroaryl ring, it is, if the nature of the adjacent atoms and groups permits, oxidation state (i.e. N ⁺ -O ^-) may be present in the. In addition, when sulfur is present in the heteroaryl ring, it may be present in the oxidized state (ie S ⁺ -O ^- or -SO _2- ), where the properties of neighboring atoms and groups allow. .. The heteroaryl group may be monocyclic or polycyclic (eg, bicyclic, tricyclic).

In some examples, the heteroaryl group is monocyclic. Examples include pyrrol, pyrazole, imidazole, triazole (eg 1,2,3-triazole, 1,2,4-triazole), tetrazole, furan, isooxazole, oxadiazole, oxadiazole (eg 1,2,3-). Oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole), thiophene, isothiazole, thiazole, thiazole (eg 1,2,3-thiazole, 1,2,4-thiazole) , 1,3,4-thiadiazole), pyridine, pyridazine, pyrimidine, pyrazine, triazine (eg 1,2,4-triazine, 1,3,5-triazine) and tetradine.

In some examples, both rings of the polycyclic heteroaryl group are aromatic. Examples include indol, isoindole, indazole, benzoimidazole, benzotriazole, benzofuran, benzoxazole, benzoisoxazole, benzoxaziazole, benzothiophene, benzothiazole, benzoisothiazole, benzothiasiazol, 1H-pyrrolo [2, 3-b] Pyridine, 1H-Pyrazolo [3,4-b] Pyridine, 3H-Imidazo [4,5-b] Pyridine, 3H- [1,2,3] Triazolo [4,5-b] Pyridine, 1H -Pyrrolo [3,2-b] Pyridine, 1H-Pyrazolo [4,3-b] Pyridine, 1H-Imidazo [4,5-b] Pyridine, 1H- [1,2,3] Triazolo [4,5- b] Pyridine, 1H-pyrrolo [2,3-c] pyridine, 1H-pyrazolo [3,4-c] pyridine, 3H-imidazo [4,5-c] pyridine, 3H- [1,2,3] triazolo [4,5-c] Pyridine, 1H-Pyrrolo [3,2-c] Pyridine, 1H-Pyrazolo [4,3-c] Pyridine, 1H-Imidazo [4,5-c] Pyridine, 1H- [1, 2,3] Triazolo [4,5-c] Pyridine, Flo [2,3-b] Pyridine, Oxazoro [5,4-b] Pyridine, Isooxazoro [5,4-b] Pyridine, [1,2,3 ] Oxaziazolo [5,4-b] Pyridine, Flo [3,2-b] Pyridine, Oxazolo [4,5-b] Pyridine, Isooxazolo [4,5-b] Pyridine, [1,2,3] Oxaziazolo [1,2,3] 4,5-b] Pyridine, Flo [2,3-c] Pyridine, Oxazolo [5,4-c] Pyridine, Isooxazoro [5,4-c] Pyridine, [1,2,3] Oxaziazolo [5,4] -c] Pyridine, Flo [3,2-c] Pyridine, Oxazolo [4,5-c] Pyridine, Isooxazolo [4,5-c] Pyridine, [1,2,3] Oxaziazolo [4,5-c] Pyridine, Thieno [2,3-b] Pyridine, Thiazolo [5,4-b] Pyridine, Isothiazolo [5,4-b] Pyridine, [1,2,3] Thiasia Zoro [5,4-b] Pyridine, Thieno [3,2-b] Pyridine, Thiazolo [4,5-b] Pyridine, Isothiazolo [4,5-b] Pyridine, [1,2,3] Thiasia Zoro [4,5-b] Pyridine, Thieno [2, 3-c] Pyridine, Thiazolo [5,4-c] Pyridine, Isothiazolo [5,4-c] Pyridine, [1,2,3] Thiasia Zoro [5,4-c] Pyridine, Thieno [3,2-c ] Pyridine , Thiazolo [4,5-c] Pyridine, Isothiazolo [4,5-c] Pyridine, [1,2,3] Thiasia Zoro [4,5-c] Pyridine, Kinolin, Isoquinolin, Synnoline, Diazanaphthalene, Kinoxaline, Phtalazine, Diazanaphthalene (eg, 1,8-naphthylene, 1,7-naphthylene, 1,6-naphthylene, 1,5-naphthylene, 2,7-naphthyline, 2,6-naphthylidine), imidazo [1,2-a] pyridine , 1H-pyrazolo [3,4-d] thiazole, 1H-pyrazolo [4,3-d] thiazole and imidazo [2,1-b] thiazole.

In another example, the polycyclic heteroaryl group may include a non-aromatic ring condensed into a heteroaryl ring (eg, cycloalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkenyl), but many. The cyclic heteroaryl group is attached to the parent structure via an atom in the aromatic ring. For example, the 4,5,6,7-tetrahydrobenzo [d] thiazole-2-yl group (where the moiety is attached to the parent structure via an aromatic carbon atom) is considered a heteroaryl group. On the other hand, 4,5,6,7-tetrahydrobenzo [d] thiazole-5-yl (the moiety is attached to the parent structure via a non-aromatic carbon atom) is considered to be a heteroaryl group. Not.

A "heterocycloalkyl" is composed of one or more heteroatoms selected from N, O and S with the remaining ring atoms being carbon (eg, 1, 2, 3 or 4 heteroatoms). It shows a fully saturated ring of non-aromatic with a number of atoms (eg, 3-10 or 3-7 membered heterocycloalkyl). Heterocycloalkyl groups can be monocyclic (ie, heteromonocyclic) or polycyclic (eg, bicyclic (ie, heterobicyclic), spiro rings and crosslinked ring systems). .. That is, the definition of a heterobicyclic is that a cycloalkyl or heteromonocyclic group 1,1-disubstituted with a heteromonocyclic ring, and a heteromonocyclic ring is another cycloalkyl or heteromonocyclic ring. A ring system that is 1,2- or 1,3-condensed on a ring (carbon or nitrogen atoms can form ring junctions (this structure is chemically possible)), In addition, the heteromonocyclic ring includes a ring system having a C _{1 to} C ₂ alkyl bridge, and a ring system in which the heteromonocyclic ring is 1,2-condensed into an aromatic or aromatic heterocycle, however. , The moiety is attached to the parent structure via a non-aromatic carbon or nitrogen atom.

Examples of monocyclic heterocycloalkyl (ie, complex monocyclic) groups include oxylanyl, aziridinyl, azetidinyl, oxetanyl, pyrrolidinyl, imidazolidinyl, pyrazoridinyl, piperidinyl, piperazinyl, morpholinyl and thiomorpholinyl.

Examples of C ₆ heterobisicryl groups include 3-azabicyclo [3.1.0] hexane-3-yl.

Examples of C _{8 to} C ₁₀ heterobicyclyl groups with aromatic rings are indoline-1-yl, isoindoline-2-yl, 1,2,3,4-tetrahydroquinoline-2-yl, 3,4-dihydroquinoline. -1 (2H) -yl and 7,8-dihydro-1,6-naphthylidine-6 (5H) -yl are included.

Examples of heterobicyclyl ring systems involving spirocyclics include 1-oxa-5-azaspiro [3.3] heptane-5-yl, 1-oxa-6-azaspiro [3.3] heptane-6-yl, 6-oxa-1-. Azaspiro [3.3] heptane-1-yl, 2-oxa-6-azaspiro [3.3] heptane-6-yl, 1,5-diazaspiro [3.3] heptane-1-yl, 1,6-diazaspiro [3.3] heptane- 6-yl, 1,6-diazaspiro [3.3] heptane-1-yl, 2,6-diazaspiro [3.3] heptane-2-yl, 1-oxa-5-azaspiro [3.4] octane-5-yl, 1- Oxa-6-azaspiro [3.4] octane-6-yl, 2-oxa-5-azaspiro [3.4] octane-5-yl, 2-oxa-6-azaspiro [3.4] octane-6-yl, 1,5-yl Diazaspiro [3.4] octane-5-yl, 1,6-diazaspiro [3.4] octane-6-yl, 2,5-diazaspiro [3.4] octane-5-yl, 2,6-diazaspiro [3.4] octane-6- Il, 1-oxa-5-azaspiro [3.5] nonane-5-yl, 1-oxa-6-azaspiro [3.5] nonane-6-yl, 1-oxa-7-azaspiro [3.5] nonane-7-yl, 2-Oxa-5-azaspiro [3.5] nonane-5-yl, 2-oxa-6-azaspiro [3.5] nonane-6-yl, 2-oxa-7-azaspiro [3.5] nonane-7-yl, 1, 5-Diazaspiro [3.5] Nonane-5-Il, 1,6-Diazaspiro [3.5] Nonane-6-Il, 1,7-Diazaspiro [3.5] Nonane-7-Il, 2,5-Diazaspiro [3.5] Nonan- 5-Il, 2,6-Diazaspiro [3.5] Nonane-6-Il, 2,7-Diazaspiro [3.5] Nonane-7-Il, 1-Oxa-5-Azaspiro [3.6] Decane-5-Il, 1- Oxa-6-azaspiro [3.6] decane-6-yl, 1-oxa-7-azaspiro [3.6] decane-7-yl, 2-oxa-5-azaspiro [3.6] decane-5-yl, 2-oxa- 6-Azaspiro [3.6] Decane-6-yl, 2-Oxa-7-Azaspiro [3.6] Decane-7-il, 1,5-Diazaspiro [3.6] Decane-5-yl, 1,6-Diazaspiro [3.6] Decan-6-Il, 1,7-Diazaspiro [3.6] Decan-7-Il 2,5-Diazaspiro [3. 6] Decane-5-yl, 2,6-Diazaspiro [3.6] Decane-6-yl, 2,7-Diazaspiro [3.6] Decane-7-yl are included.

Examples of heterobicyclyl ring systems containing C _{1 to} C ₄ crosslinked alkylene include 2-azabicyclo [2.2.1] heptane-2-yl, 2-azabicyclo [3.2.1] octane-2-yl, 3-azabicyclo [3.2]. .1] Octane-3-yl and 6-azabicyclo [3.2.1] Octane-6-yl are included.

When nitrogen is present in a heterocycloalkyl ring, which, when the nature of the atoms and groups are in close proximity so permits, the oxidation state (i.e. N ⁺ -O ^-) may be present in the. Examples include piperidinyl N-oxide and morpholinyl-N-oxide. In addition, when sulfur is present in the heterocycloalkyl ring, it is present in the oxidized state (ie S ⁺ -O ^- or -SO _2- ), where the properties of neighboring atoms and groups allow. You may. Examples include thiomorpholine S-oxide and thiomorpholine S, S-dioxide.

“Oxo” means (= O) or (O).

"Nitro" means -NO ₂ .

The term "replaced" is used herein to mean that any one or more hydrogens on a specified atom or group have been replaced with one selected from the groups shown. However, the normal valency of the specified atom cannot be exceeded. When the substituent is oxo (ie = O), then the two hydrogens on the atom are replaced. Substituent and / or variable combinations are only acceptable if such combinations result in stable compounds or useful synthetic intermediates. A stable compound or stable structure is meant to suggest a compound that is robust enough to survive isolation from the reaction mixture and subsequent formulation as a drug with at least practical utility. Unless otherwise specified, substituents are named according to their core structure. For example, when (cycloalkyl) alkyl is listed as a possible substituent, it will be understood that the attachment point of this substituent to the core structure is in the alkyl moiety.

The term (including, without limitation, C ₁ -C ₄ alkyl) "substituted by which" alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl, unless clearly been made otherwise defined, respectively, alkyl, cycloalkyl Refers to alkyl, aryl, heterocycloalkyl and heteroaryl, where one or more (eg, up to 5, for example, up to 3) hydrogen atoms are independently -R ^a , -OR ^b , -O (. C ₁ -C ₂ alkyl) O-(e.g. methylenedioxy -), - SR ^b, guanidine _{(-NHC (= NH) NH 2} ), have been replaced by substituents independently selected from guanidine, wherein One or more of the guanidine hydrogens are C _{1 to} C ₄ alkyl groups, -NR ^b R ^c , halo, cyano, oxo (as substituents for heterocycloalkyl), nitro, -COR ^b , -CO ₂ R ^b , -CONR ^b R ^c , -OCOR ^b , -OCO ₂ R ^a , -OCONR ^b R ^c , -NR ^c COR ^b , -NR ^c CO ₂ R ^a , -NR ^c CONR ^b R ^c , -SOR ^a , -SO ₂ R ^a , -SO ₂ NR ^b R ^c , and -NR ^c SO ₂ R ^a
Here, ^Ra is selected from C _{1 to} C ₆ alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl.
R ^b is selected from H, C _{1 to} C ₆ alkyl, aryl and heteroaryl, and
R ^c is selected from hydrogen and C _{1 to} C ₄ alkyl, or
R ^b and R ^c , and the nitrogen to which they are attached, form heterocycloalkyl groups, where each C _1- C ₆ alkyl, cycloalkyl, aryl, heterocycloalkyl and heteroaryl are: C _{1 to} C ₄ alkyl, C _{3 to} C ₆ cycloalkyl, aryl, heteroaryl, aryl-C _{1 to} C ₄ alkyl-, heteroaryl-C _{1 to} C ₄ alkyl-, C _{1 to} C ₄ haloalkyl-,- OC _{1 to} C ₄ alkyl, -OC _{1 to} C ₄ alkylphenyl, -C _{1 to} C ₄ alkyl-OH, -C _{1 to} C ₄ alkyl -OC _{1 to} C ₄ alkyl, -OC _{1 to} C ₄ haloalkyl, halo , -OH, -NH ₂ , -C _{1 to} C ₄ alkyl-NH ₂ , -N (C _{1 to} C ₄ alkyl) (C _{1 to} C ₄ alkyl), -NH (C _{1 to} C ₄ alkyl),- N (C _{1 to} C ₄ alkyl) (C _{1 to} C ₄ alkylphenyl), -NH (C _{1 to} C ₄ alkylphenyl), cyano, nitro, oxo (as substituents for heteroaryl), -CO ₂ H, -C (O) OC _{1 to} C ₄ alkyl, -CON (C _{1 to} C ₄ alkyl) (C _{1 to} C ₄ alkyl), -CONH (C _{1 to} C ₄ alkyl), -CONH ₂ , -NHC (O) (C _{1 to} C ₄ alkyl), -NHC (O) (phenyl), -N (C _{1 to} C ₄ alkyl) C (O) (C _{1 to} C ₄ alkyl), -N (C ₁ to C ₄ alkyl) C (O) (phenyl), -C (O) C _{1 to} C ₄ alkyl, -C (O) C _{1 to} C ₄ phenyl, -C (O) C _{1 to} C ₄ haloalkyl, -OC (O) C ₁ ~C ₄ alkyl, -SO ₂ (C ₁ ~C ₄ alkyl), - SO _{2 (phenyl), - SO 2 (C 1} ~C 4 _{haloalkyl), - SO 2 NH 2,} -SO 2 NH (C ₁ -C ₄ alkyl), - SO ₂ NH _{(phenyl), - NHSO 2 (C 1} ~C 4 alkyl), - NHSO ₂ from (phenyl), and -NHSO ₂ (C ₁ ~C ₄ haloalkyl) It is optionally substituted with one or more independently selected substituents (eg, one, two or three).

The compounds described herein include, but are not limited to, their optical isomers, racemates, and other mixtures thereof. In such situations, a single enantiomer or diastereomer, an optically active form, can be obtained by asymmetric synthesis or by racemic division. The racemate is divided by conventional methods such as crystallization in the presence of a dividing agent or chromatography using, for example, a chiral high pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) column. Can be achieved. In addition, such compounds include Z- and E-forms (or cis- and trans-forms) of compounds with carbon-carbon double bonds. Where the compounds described herein are present in various tautomeric forms, the term "compound" is intended to include all tautomeric forms of the compound. Such compounds also include crystalline forms, including polymorphs and clathrates. Similarly, the term "salt" is intended to include all tautomeric and crystalline forms of a compound.

If the configuration of a single diastereomer is not known, the configuration may be, for example, an unknown chiral center (s) shown as D1 (diastereomers 1) and D2 (diastereomers 2) as an asterisk. Is displayed. For example, D1 N-((R) -1-((abs) -3- (difluoromethoxy) piperidin-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2 , 4-Oxadiazole-3-yl) benzamide and D2 N-((R) -1-((abs) -3- (difluoromethoxy) piperidin-1-yl) propan-2-yl) -4-( 5- (Trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide is a single diastereomer, and the configuration of one stereocenter is absolutely known (1). The molecular configuration of the second chiral center is absolute but unknown (drawn as a single bond with asterisk), that is, the opposite of the unknown center for D1 vs. D2. It is an arrangement.

A single isomer has been isolated for a compound with three chiral centers and one known stereocenter, and the absolute configuration of the other two centers is unknown, but the relative configuration is cis. And, for example, if it is known to be a homochiral azabicycloheptanyl ring system, the compound is drawn with an unknown chiral center (s) labeled as asterisk and is appropriately named, ie, D1. : N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl) propan-2-yl) -4- (5- (trifluoro) Methyl) -1,2,4-oxadiazole-3-yl) benzamide; and D2: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] Heptane-6-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide.

"Pharmaceutically acceptable salts" include salts with inorganic acids such as hydrochlorides, phosphates, diphosphates, hydrobromates, sulfates, sulfates, nitrates, and similar salts. , And salts with organic acids such as malate, maleate, fumarate, tartrate, succinate, citrate, acetate, lactate, methanesulfonate, p-toluenesulfonate, Alcanates such as 2-hydroxyethyl sulfonate, benzoate, salicylate, stearate, and acetate, HOOC- (CH ₂ ) _q -COOH (where q is 0-4 in the formula) , And similar salts, but not limited to these. Similarly, pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium and ammonium.

In addition, when the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, if the product is a free base, the addition salt, especially the pharmaceutically acceptable addition salt, will have the free base in a suitable organic solvent according to prior art methods of preparing acid addition salts from base compounds. It may be produced by dissolving and treating the solution with an acid. Those skilled in the art will recognize a variety of synthetic methodologies that may be used to prepare non-toxic free bases or non-toxic, pharmaceutically acceptable addition salts.

As used herein, the terms "group", "radical" or "fragment" are synonymous and are intended to indicate a functional group or fragment of a molecule that is capable of binding or binding to other fragments of the molecule. To.

The term "active agent" is used to indicate a compound having biological activity or a pharmaceutically acceptable salt thereof. In some embodiments, the "active agent" is a compound having pharmaceutically usefulness or a pharmaceutically acceptable salt thereof. For example, the active agent may be a therapeutic agent for anti-neurodegeneration.

The term "therapeutically effective amount" is effective in imparting therapeutic benefits such as remission of symptoms, delay in disease progression, or prevention of disease when administered to human or non-human patients. Means the amount, for example, a therapeutically effective amount may be sufficient to reduce the signs of a disease that is responsive to inhibition of HDAC activity.

As used herein, the terms "histone deacetylase" and "HDAC" are among the family of enzymes that remove the N ^ε -acetyl group from the ε-amino group of the lysine residue of a protein (eg, histone or tubulin). It is intended to refer to any one of. Unless otherwise specified by the context, the term "histone" means to refer to any histone protein, including H1, H2A, H2B, H3, H4 and H5 from any species. In some embodiments, histone deacetylases are human HDACs, including, but not limited to, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-9 and HDAC-10. In some embodiments, at least one histone deacetylase is selected from HDAC-4, HDAC-5, HDAC-7 and HDAC-9. In some embodiments, histone deacetylase is a class IIa HDAC. In some embodiments, the histone deacetylase is HDAC-4. In some embodiments, the histone deacetylase is HDAC-5. In some embodiments, histone deacetylases are derived from protozoan or fungal sources.

The terms "histone deacetylase inhibitor" and "histone deacetylase inhibitor" are compounds described herein or capable of interacting with histone deacetylase to inhibit its enzymatic activity. It is intended to mean that pharmaceutically acceptable salt.

The terms "HDAC-mediated state or disorder" or "histone deacetylase-mediated state or disorder" are used herein where the action of HDAC and / or HDAC is, eg, the beginning and progression of that state. , A condition or disorder that is important or necessary for expression, etc., or a condition that is known to be treated with an HDAC inhibitor (eg, tricostatin A).

The term "effect" describes a change or absence of change in cell phenotype or cell proliferation. The "effect" can also explain a change or absence of change in the catalytic activity of HDACs. The "effect" can also explain the change or absence of change in the interaction between HDACs and their native binding partners.

The term "inhibiting the enzymatic activity of histone deacetylase" or "inhibiting histone deacetylase" reduces the ability of histone deacetylase and, but is not limited to, proteins such as histones or tubulin. It is intended to mean removing the acetyl group from. The activity of histone deacetylase, the concentration of inhibitor that reduces by 50% of the uninhibited enzyme activity is determined as an IC ₅₀ value. In some embodiments, such a reduction in histone deacetylase activity is at least 50%, eg at least about 75%, eg at least 90%. In some embodiments, histone deacetylase activity is reduced by at least 95%, eg, at least 99%. In some embodiments, the compound and IC ₅₀ values of a pharmaceutically acceptable salt thereof as described herein is less than 100 nanomolar. In some embodiments, the compounds described herein and IC ₅₀ v values of a pharmaceutically acceptable salt thereof is a 100 nanomolar to 1 micromolar. In some embodiments, the compounds described herein and IC ₅₀ v values of a pharmaceutically acceptable salt thereof is 1 to 25 micromolar.

In some embodiments, such inhibition is specific, i.e., an inhibition of a histone deacetylase inhibitor is required to bring about another unrelated biological effect of histone deacetylase. At concentrations below the drug's concentration, it reduces the ability to remove acetyl groups from the protein. In some embodiments, the concentration of inhibitor required for histone deacetylase inhibitory activity is at least 2-fold lower than the concentration required to produce an unrelated biological effect, eg at least 5. Twice lower, say at least 10 times lower, say at least 20 times lower.

"Treatment" or "treat" means any treatment of a diseased condition in a patient,
a) Preventing the disease, that is, preventing the development of clinical signs of the disease
b) Inhibiting the disease
c) Delaying or stopping the onset of clinical signs and / or
d) It involves alleviating the disease, that is, causing regression of clinical signs.

"Subject" or "patient" refers to an animal, such as a mammal, that is or will be the subject of treatment, observation or experimentation. The methods described herein may be useful in both human therapy and veterinary applications. In some embodiments, the subject is a mammal, and in some embodiments, the subject is a human.

For clarity, it is understood that some of the features described herein that are described in relation to different embodiments may also be provided in combination in a single embodiment. I want to. Conversely, for brevity, the various features described herein, described in connection with a single embodiment, can also be provided separately or in any suitable subcombination. All combinations of embodiments relating to the chemical groups represented by the variables contained in Formula I are such that such combinations result in stable compounds (ie, isolated, characterized and tested for biological activity. To the extent that each and every combination is included, as if individually and explicitly listed. In addition, all subcombinations of chemical groups listed in the embodiments that describe such variables, as well as all uses and medical applications described herein, such as conditions or disorders mediated by HDAC. Sub-combinations are also specifically included herein as if each and every sub-combination of chemical groups and sub-combinations of use and medical application were individually and explicitly listed herein. In addition, some embodiments include any combination of one or more additional agents disclosed herein, as if each and every combination were listed individually and explicitly.

Equation I

[式中、
Wは、N又はCR⁵であり;Xは、N又はCR⁶であり;Yは、N又はCR⁷であり;Zは、N又はCR⁸であり;ただし、W、X、Y、及びZのうち2つ以下は、Nであり;
R¹は、H及びC₁〜C₃アルキルから選択され;
R²は、C₁〜C₂ハロアルキル又は3若しくは4員のシクロアルキルで任意選択で置換されているC₂〜C₃アルキレンであり;
R³及びR⁴は、これらが結合している窒素原子と一緒になって、
4、5、6、若しくは7員の複素単環式基、又は
6、7、8、9、若しくは10員の複素二環式基を形成し、
それらのそれぞれは、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換され、ここでアリール及びヘテロアリールは、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換され、
ただし、R³及びR⁴が、これらが結合している窒素原子と一緒になって、5又は6員の複素単環式基を形成する場合、
i)R²は、C₁〜C₂ハロアルキル又は3若しくは4員のシクロアルキルで置換されているC₂〜C₃アルキレンである、又は
ii)R⁸は、ハロ若しくはC₁〜C₃アルキルである、又は
iii)5若しくは6員の複素単環式基は、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3若しくは4員のシクロアルコキシ、3若しくは4員のシクロアルキル、3若しくは4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で置換され、ここでアリール及びヘテロアリールは、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換され;
R⁵、R⁶、R⁷及びR⁸は、H、C₁〜C₄アルキル、C₁〜C₄ハロアルキル、及びハロからそれぞれ独立に選択される]
の化合物又はその薬学的に許容される塩が提供される。

[During the ceremony,
W is N or CR ⁵ ; X is N or CR ⁶ ; Y is N or CR ⁷ ; Z is N or CR ⁸ ; where W, X, Y, and Z Two or less of them are N;
R ¹ is selected from H and C _{1 to} C ₃ alkyl;
R ² is C ₂ -C ₃ alkylene which is optionally substituted with C ₁ -C ₂ haloalkyl, or 3 or 4-membered cycloalkyl;
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
4, 5, 6, or 7-membered complex monocyclic group, or
Form 6, 7, 8, 9, or 10-membered complex bicyclic groups,
Each of them is C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, It is optionally substituted with 1 to 5 substituents independently selected from 3- or 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, where the aryl and heteroaryl are C ₁ Further optionally further substituted with 1 to 5 substituents independently selected from ~ C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively.
However, if R ³ and R ⁴ combine with the nitrogen atom to which they are attached to form a 5- or 6-membered complex monocyclic group.
i) R ² is a C ₂ -C ₃ alkylene substituted with C ₁ -C ₂ haloalkyl, or 3 or 4-membered cycloalkyl, or
ii) R ⁸ is halo or C _{1 to} C ₃ alkyl, or
iii) 5- or 6-membered heteromonocyclic groups are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy. , 3 or 4 membered cycloalkyl, 3 or 4 membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, each substituted with 1-5 substituents independently selected, where aryl and Heteroaryls are optionally further substituted with 1 to 5 substituents, each independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo;
R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from H, C _{1 to} C ₄ alkyl, C _{1 to} C ₄ haloalkyl, and halo, respectively]
Compound or a pharmaceutically acceptable salt thereof is provided.

In some embodiments, R ¹ is selected from H and methyl. In some embodiments, R ¹ is H.

In some embodiments, R ² is a C _2- C ₃ alkylene optionally substituted with a 3- or 4-membered cycloalkyl. In some embodiments, R ² is selected from-(CH ₂ ) _2- and-CH (CH ₃ ) CH _2- .

In some embodiments, R ⁵ is H.

In some embodiments, R ⁶ is H.

In some embodiments, R ⁷ is H.

In some embodiments, R ⁸ is selected from H, halo, and methyl.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, Independently selected from C _{1 to} C ₃ haloalkyl, 3- or 4-membered cycloalkoxy, 3- or 4-membered cycloalkyl, 3- or 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. It forms a 4- or 7-membered heteromonocyclic group optionally substituted with 1 to 5 substituents, where the aryl and heteroaryl are C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, And halos are further optionally further substituted with 1-5 substituents, each independently selected.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, ₁ to 5 substituents independently selected from C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 or 4 member heterocycloalkyl, aryl, and heteroaryl, respectively. Form a 4- or 7-membered heteromonocyclic group optionally substituted with, where the aryls and heteroaryls are independent of C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. It is further optionally substituted with 1 to 5 substituents selected.

In some embodiments, R ³ and R ⁴ are selected independently from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and aryl, respectively, together with the nitrogen atom to which they are attached. It forms a 4- or 7-membered heteromonocyclic group optionally substituted with 1 to 5 substituents, where the aryls are C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and. It is further optionally further substituted with 1 to 5 substituents, each independently selected from the halo.

In some embodiments, R ³ and R ⁴ are selected independently from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and phenyl, respectively, together with the nitrogen atom to which they are attached. It forms a 4- or 7-membered heteromonocyclic group optionally substituted with 1 to 5 substituents, where the phenyl is C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and. It is further optionally further substituted with 1 to 5 substituents, each independently selected from the halo.

In some embodiments, R ³ and R ⁴ are optional with 1-5 substituents, each independently selected from methyl, difluoromethoxy, and phenyl, together with the nitrogen atom to which they are attached. It forms a 4- or 7-membered heteromonocyclic group substituted by selection.

In some embodiments, R ³ and R ⁴ are selected from 3-phenylazetidine-1-yl, and azepan-1-yl, together with the nitrogen atom to which they are attached. It forms a 7-membered complex monocyclic group.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 5- or 6-membered complex monocyclic group, and R ² is C ₁ to C. It is a C _2- C ₃ alkylene substituted with _2- haloalkyl or 3- or 4-membered cycloalkyl, for example, R ² is a C _2- C ₃ alkylene substituted with cyclopropyl.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, Independently selected from C _{1 to} C ₃ haloalkyl, 3- or 4-membered cycloalkoxy, 3- or 4-membered cycloalkyl, 3- or 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. It forms a 5- or 6-membered heteromonocyclic group optionally substituted with 1 to 5 substituents, where the aryl and heteroaryl are C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and further optionally substituted with one to five substituents each independently selected from halo, R ² is, C ₂ -C substituted with C ₁ -C ₂ haloalkyl, or 3 or 4-membered cycloalkyl It is a _3- alkylene, for example, R ² is a C _2- C ₃ alkylene substituted with cyclopropyl.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, ₁ to 5 substituents independently selected from C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 or 4 member heterocycloalkyl, aryl, and heteroaryl, respectively. Form a 5- or 6-membered heteromonocyclic group optionally substituted with, where aryl and heteroaryl are independent of C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. Further optionally further substituted with 1 to 5 substituents selected, R ² is a C _{2 to} C ₃ alkylene substituted with C _{1 to} C ₂ haloalkyl or 3 or 4 membered cycloalkyl, eg , R ² are C _2- C ₃ alkylenes substituted with cyclopropyl.

In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are attached, are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and aryl, respectively. Form a 5- or 6-membered heteromonocyclic group optionally substituted with 1 to 5 substituents, where the aryls are C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and. Further optionally further substituted with 1 to 5 substituents, each independently selected from the halo, R ² is substituted with C _{1 to} C ₂ haloalkyl or 3 or 4 membered cycloalkyl C _{2 to} C ₃ It is an alkylene, for example, R ² is a C _{2 to} C ₃ alkylene substituted with cyclopropyl.

In some embodiments, R ³ and R ⁴ are selected independently from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and phenyl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group optionally substituted with 1 to 5 substituents, where phenyl is C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and Further optionally further substituted with 1 to 5 substituents, each independently selected from halo, R ² is substituted with C _{1 to} C ₂ haloalkyl or 3 or 4 membered cycloalkyl C _{2 to} C ₃ It is an alkylene, for example, R ² is a C _{2 to} C ₃ alkylene substituted with cyclopropyl.

In some embodiments, R ³ and R ⁴ are optional with 1-5 substituents, each independently selected from methyl, difluoromethoxy, and phenyl, together with the nitrogen atom to which they are attached. Forming a selectively substituted 5- or 6-membered heteromonocyclic group, R ² is a C _2- C _3- alkylene substituted with C _1- C _2- haloalkyl or 3- or 4-membered cycloalkyl. Yes, for example, R ² is a C _2- C ₃ alkylene substituted with cyclopropyl.

In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are attached, are a 5- or 6-membered complex selected from pyrrolidine-1-yl and piperidin-1-yl. to form a monocyclic group, each of which methyl, difluoromethoxy, and optionally substituted with one substituent selected from phenyl, R ² is a C ₁ -C ₂ haloalkyl, or 3 or 4-membered It is a C _2- C ₃ alkylene substituted with cycloalkyl, for example, R ² is a C _2- C ₃ alkylene substituted with cyclopropyl.

In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are attached, are pyrrolidine-1-yl, 2-methyl-pyrrolidin-1-yl, and 3- (difluoromethoxy). ) Forming a 5- or 6-membered heteromonocyclic group selected from piperidine-1-yl, where R ² is substituted with C _1- C _2- haloalkyl or 3- or 4-membered cycloalkyl C _2- It is a C ₃ alkylene, for example, R ² is a C _{2 to} C ₃ alkylene substituted with cyclopropyl.

In some embodiments, R ³ and R ⁴ combine with the nitrogen atom to which they are attached to form a 5- or 6-membered complex monocyclic group, and R ⁸ is a halo or C ₁ ~ C ₃ alkyl.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, Independently selected from C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 or 4 member heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. It forms a 5- or 6-membered heteromonocyclic group optionally substituted with 1 to 5 substituents, where the aryl and heteroaryl are C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, And optionally further substituted with 1-5 substituents, each independently selected from the halo, R ⁸ is a halo or a C _1- C ₃ alkyl, eg, methyl.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, ₁ to 5 substituents independently selected from C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 or 4 member heterocycloalkyl, aryl, and heteroaryl, respectively. To form a 5- or 6-membered heteromonocyclic group optionally substituted with, aryl and heteroaryl are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. Further optionally further substituted with 1 to 5 substituents, R ⁸ is halo or C _{1 to} C ₃ alkyl, eg methyl.

In some embodiments, R ³ and R ⁴ are selected independently from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and aryl, respectively, together with the nitrogen atom to which they are attached. Form a 5- or 6-membered heteromonocyclic group optionally substituted with 1 to 5 substituents, where the aryls are C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and. Further optionally further substituted with 1 to 5 substituents, each independently selected from the halo, R ⁸ is a halo or a C _{1 to} C ₃ alkyl, eg, methyl.

In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are attached, are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and phenyl, respectively. It forms a 5- or 6-membered heteromonocyclic group optionally substituted with 1 to 5 substituents, where the phenyl is C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo. Further optionally further substituted with 1-5 substituents, each independently selected from, R ⁸ is halo or C _1- C ₃ alkyl, eg, methyl.

In some embodiments, R ³ and R ⁴ are optional with 1-5 substituents, each independently selected from methyl, difluoromethoxy, and phenyl, together with the nitrogen atom to which they are attached. Forming a selectively substituted 5- or 6-membered heteromonocyclic group, R ⁸ is halo or C _{1 to} C ₃ alkyl, eg, methyl.

In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are attached, are 5- or 6-membered complex selected from pyrrolidine-1-yl and piperidin-1-yl. It forms a monocyclic group, each of which is optionally substituted with one substituent selected from methyl, difluoromethoxy, and phenyl, where R ⁸ is halo or C _{1 to} C ₃ alkyl, eg. , Methyl.

In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are attached, are pyrrolidine-1-yl, 2-methyl-pyrrolidin-1-yl, and 3- (difluoromethoxy). ) Forming a 5- or 6-membered heteromonocyclic group selected from piperidine-1-yl, R ⁸ is halo or C _{1 to} C ₃ alkyl, eg, methyl.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, Independently selected from C _{1 to} C ₃ haloalkyl, 3- or 4-membered cycloalkoxy, 3- or 4-membered cycloalkyl, 3- or 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. It forms a 5- or 6-membered heteromonocyclic group substituted with 1 to 5 substituents, where aryls and heteroaryls are from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo. It is further optionally substituted with 1 to 5 substituents, each independently selected.

In some embodiments, R ³ and R ⁴ are selected independently from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and aryl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group substituted with 1 to 5 substituents, where the aryl is from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. It is further optionally substituted with 1 to 5 independently selected substituents.

In some embodiments, R ³ and R ⁴ are selected independently from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and phenyl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group substituted with 1 to 5 substituents, where the phenyl is derived from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. It is further optionally substituted with 1 to 5 independently selected substituents.

In some embodiments, R ³ and R ⁴ are substituted with 1-5 substituents, each independently selected from methyl, difluoromethoxy, and phenyl, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group.

In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are attached, are 5- or 6-membered complex selected from pyrrolidine-1-yl and piperidin-1-yl. It forms monocyclic groups, each of which is substituted with one substituent selected from methyl, difluoromethoxy, and phenyl.

In some embodiments, R ³ and R ⁴ , together with the nitrogen atom to which they are attached, are 2-methyl-pyrrolidin-1-yl, and 3- (difluoromethoxy) piperidin-1-yl. Form a 5- or 6-membered complex monocyclic group selected from.

In some embodiments, R ³ and R ⁴ combine with the nitrogen atom to which they are attached to form (2S) -methyl-pyrrolidin-1-yl.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 6, 7, 8, 9, or 10-membered heterobicyclic group, which is complex. Bicyclic groups are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl. , 3 or 4 membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively, optionally substituted with 1 to 5 substituents, wherein the aryl and heteroaryl are C. It is further optionally further substituted with 1 to 5 substituents, each independently selected from _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached,
1-Azaspiracid [3.3] Heptane-1-yl,
3-Azabicyclo [3.1.0] Hexane-3-yl,
3-Azabicyclo [3.2.0] Heptane-3-yl,
3-Azabicyclo [3.2.1] Heptane-3-yl,
3-Azabicyclo [3.2.1] Octane-3-yl,
3,4-dihydroisoquinoline-2 (1H) -yl,
3,4-Dihydro-2,7-Diazanaphthalene-2 (1H) -Il,
5-Azaspiracid [2.4] Heptane-5-Il,
5-Azaspiracid [2.5] Octane-5-Il,
6-Azaspiracid [2.5] Octane-6-Il,
1-Azaspiracid [3.3] Heptane-1-yl,
6-Azabicyclo [3.2.0] Heptane-6-Il,
Forming 6, 7, 8, 9, or 10-membered complex bicyclic groups selected from isoindoline-2-yl and octahydrocyclopenta [c] pyrrole-2-yl,
C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 respectively. Alternatively, they are optionally substituted with 1 to 5 substituents independently selected from the 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, wherein the aryl and heteroaryl are C ₁ to. It is further optionally further substituted with 1 to 5 substituents, each independently selected from C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached,
1-Azaspiracid [3.3] Heptane-1-yl,
3-Azabicyclo [3.1.0] Hexane-3-yl,
3-Azabicyclo [3.2.0] Heptane-3-yl,
3-Azabicyclo [3.2.1] Heptane-3-yl,
3-Azabicyclo [3.2.1] Octane-3-yl,
3,4-dihydroisoquinoline-2 (1H) -yl,
3,4-Dihydro-2,7-Diazanaphthalene-2 (1H) -Il,
5-Azaspiracid [2.4] Heptane-5-Il,
5-Azaspiracid [2.5] Octane-5-Il,
6-Azaspiracid [2.5] Octane-6-Il,
1-Azaspiracid [3.3] Heptane-1-yl,
6-Azabicyclo [3.2.0] Heptane-6-Il,
Forming 6, 7, 8, 9, or 10-membered complex bicyclic groups selected from isoindoline-2-yl and octahydrocyclopenta [c] pyrrole-2-yl,
Each of them is one or two substituents independently selected from C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, and carboxy, respectively. It has been replaced by arbitrary selection.

In some embodiments, R ³ and R ⁴ together with the nitrogen atom to which they are attached,
1-Azaspiracid [3.3] Heptane-1-yl,
3-Azabicyclo [3.1.0] Hexane-3-yl,
3-Azabicyclo [3.2.0] Heptane-3-yl,
3-Azabicyclo [3.2.1] Heptane-3-yl,
3-Azabicyclo [3.2.1] Octane-3-yl,
3,4-dihydroisoquinoline-2 (1H) -yl,
3,4-Dihydro-2,7-Diazanaphthalene-2 (1H) -Il,
5-Azaspiracid [2.4] Heptane-5-Il,
5-Azaspiracid [2.5] Octane-5-Il,
6-Azaspiracid [2.5] Octane-6-Il,
1-Azaspiracid [3.3] Heptane-1-yl,
6-Azabicyclo [3.2.0] Heptane-6-Il,
Forming 6, 7, 8, 9, or 10-membered complex bicyclic groups selected from isoindoline-2-yl and octahydrocyclopenta [c] pyrrole-2-yl,
Each of which is optionally substituted with one or two substituents each independently selected from C ₁ -C ₃ alkyl.

Also, Equation II

[式中、R¹、R²、R³、R⁴、R⁵、R⁶、R⁷、及びR⁸は、本明細書に記載した通りである]
の化合物又はその薬学的に許容される塩が提供される。

[In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are as described herein].
Compound or a pharmaceutically acceptable salt thereof is provided.

Also, Equation III

[式中、R¹、R³、R⁴、R⁵、R⁶、R⁷、及びR⁸は、本明細書に記載した通りである]
の化合物又はその薬学的に許容される塩が提供される。

[In the formula, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , and R ⁸ are as described herein].
Compound or a pharmaceutically acceptable salt thereof is provided.

Also, Equation IV

[式中、R³及びR⁴は、本明細書に記載した通りである]
の化合物、又は式VIのその薬学的に許容される塩、若しくはその薬学的に許容される塩が提供される。

[In the formula, R ³ and R ⁴ are as described herein]
, Or its pharmaceutically acceptable salt of formula VI, or its pharmaceutically acceptable salt.

Also, formula V

[式中、R¹、R²、R³、R⁴、R⁵、R⁷、及びR⁸は、本明細書に記載した通りである]
の化合物又はその薬学的に許容される塩が提供される。

[In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁷ , and R ⁸ are as described herein].
Compound or a pharmaceutically acceptable salt thereof is provided.

Also, the expression VI

[式中、R¹、R³、R⁴、R⁵、R⁷、及びR⁸は、本明細書に記載した通りである]
の化合物又はその薬学的に許容される塩が提供される。

[In the formula, R ¹ , R ³ , R ⁴ , R ⁵ , R ⁷ , and R ⁸ are as described herein]
Compound or a pharmaceutically acceptable salt thereof is provided.

Also, Equation VII

[式中、R³及びR⁴は、本明細書に記載した通りである]
の化合物又はその薬学的に許容される塩が提供される。

[In the formula, R ³ and R ⁴ are as described herein]
Compound or a pharmaceutically acceptable salt thereof is provided.

Also,
(2S) -2-Methyl-1-((R) -2-(3-Methyl-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl ) Pyrrolidine-1-iumformate;
N-(2- (3-azabicyclo [3.2.1] octane-3-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
(R) -N- (1- (isoindoline-2-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide ;
N-((2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
(S) -N- (1-Cyclopropyl-2- (pyrrolidin-1-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide ;
(R) -N- (1-Cyclopropyl-2- (pyrrolidin-1-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide ;
(R) -N- (1- (3,4-dihydroisoquinoline-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
(R) -N- (1- (3-Phenylazetidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3- Il) Benzamide;
D1: N-((R) -1-((abs) -3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2, 4-Oxadiazole-3-yl) benzamide;
D2: N-((R) -1-((abs) -3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2, 4-Oxadiazole-3-yl) benzamide;
(R) -N- (1- (5-azaspiro [2.5] octane-5-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
(R) -N- (1- (6-azaspiro [2.5] octane-6-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
(R) -N- (1- (azepan-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
(R) -N- (1- (1-azaspiro [3.3] heptane-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
(R) -N- (1- (5-azaspiro [2.4] heptane-5-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
N-((R) -1- (3-azabicyclo [3.2.1] octane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
2-((R) -2-(4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl) octahydrocyclopenta [c] pyrrole-2- Iumformate;
(R) -N- (1- (3,4-dihydro-2,7-naphthylidine-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2 , 4-Oxadiazole-3-yl) benzamide;
N-((2R) -1- (3-azabicyclo [3.2.0] heptane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
D1: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl) propan-2-yl) -4- (5- (tri) Fluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
D2: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl) propan-2-yl) -4- (5- (tri) Fluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
N-((2R) -1- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1, 2,4-Oxadiazole-3-yl) benzamide;
(2S) -1-((R) -2- (3-Fluoro-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl) -2- Methylpyrrolidine-1-iamformate; and
N-((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) -5- (5- (trifluoromethyl) -1,2,4-oxadiazole A compound selected from -3-yl) picoline amide or a pharmaceutically acceptable salt thereof is provided.

Also,
(2S) -2-Methyl-1-((R) -2-(3-Methyl-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl ) Pyrrolidine-1-iumformate;
N-(2- (3-azabicyclo [3.2.1] octane-3-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
(R) -N- (1- (isoindoline-2-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide ;
N-((2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
(S) -N- (1-Cyclopropyl-2- (pyrrolidin-1-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide ;
(R) -N- (1-Cyclopropyl-2- (pyrrolidin-1-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide ;
(R) -N- (1- (3,4-dihydroisoquinoline-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
(R) -N- (1- (3-Phenylazetidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3- Il) Benzamide;
D1: N-((R) -1-((abs) -3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2, 4-Oxadiazole-3-yl) benzamide;
D2: N-((R) -1-((abs) -3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2, 4-Oxadiazole-3-yl) benzamide;
(R) -N- (1- (5-azaspiro [2.5] octane-5-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
(R) -N- (1- (6-azaspiro [2.5] octane-6-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
(R) -N- (1- (azepan-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
(R) -N- (1- (1-azaspiro [3.3] heptane-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
(R) -N- (1- (5-azaspiro [2.4] heptane-5-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
N-((R) -1- (3-azabicyclo [3.2.1] octane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
2-((R) -2-(4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl) octahydrocyclopenta [c] pyrrole-2- Iumformate;
(R) -N- (1- (3,4-dihydro-2,7-naphthylidine-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2 , 4-Oxadiazole-3-yl) benzamide;
N-((2R) -1- (3-azabicyclo [3.2.0] heptane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
D1: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl) propan-2-yl) -4- (5- (tri) Fluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
D2: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl) propan-2-yl) -4- (5- (tri) Fluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
N-((2R) -1- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1, 2,4-Oxadiazole-3-yl) benzamide;
(2S) -1-((R) -2- (3-Fluoro-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl) -2- Methylpyrrolidine-1-iamformate;
N-((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) -5- (5- (trifluoromethyl) -1,2,4-oxadiazole -3-Il) Picoline amide;
3-Methyl-N-((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4 -Oxadiazole-3-yl) benzamide;
N-((2R) -1- (hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4- Oxadiazole-3-yl) benzamide;
3-Fluoro-N-((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4 -A compound selected from oxadiazole-3-yl) benzamide or a pharmaceutically acceptable salt thereof is provided.

Methods of obtaining the compounds described herein or pharmaceutically acceptable salts thereof will be apparent to those of skill in the art and suitable procedures are described, for example, in the examples below and as cited herein. It is described in the literature.

Also provided is a method of inhibiting at least one histone deacetylase. Also provided are the use of at least one compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for inhibiting at least one histone deacetylase. Also provided are at least one compound described herein or a pharmaceutically acceptable salt thereof for use in a method for inhibiting at least one histone deacetylase. In some embodiments, at least one histone deacetylase is a class IIa HDAC. In some embodiments, at least one histone deacetylase has homology with yeast HDA1. In some embodiments, the at least one histone deacetylase is selected from HDAC-4, HDAC-5, HDAC-7 and HCAC-9. In some embodiments, the inhibition is in the cell. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are selective to inhibit at least one class II histone deacetylase. In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are HDAC-4 and / or selective inhibitors of HDAC-5.

Also, in a subject in need of such treatment, a method of treating a condition or disorder mediated by HDAC, wherein a therapeutically effective amount of at least one compound described herein or a combination thereof. Methods are provided that include administering a pharmaceutically acceptable salt. It is also mediated by HDACs in subjects in need of such treatment, including the step of administering to the subject a therapeutically effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. A method of treating a condition or disorder is provided. Also provided are the use of at least one compound described herein or a pharmaceutically acceptable salt thereof in the manufacture of a pharmaceutical product for the treatment of an HDAC-mediated condition or disorder. Also provided are at least one compound described herein or a pharmaceutically acceptable salt thereof for use in methods for the treatment of the human or animal body by therapy. Also provided are at least one compound described herein or a pharmaceutically acceptable salt thereof for use in methods for the treatment of conditions or disorders.

Inhibition of at least one histone deacetylase in a patient in need thereof, including the step of administering to the patient a therapeutically effective amount of the compound or pharmaceutically acceptable salt thereof described herein. A method of treating a condition or disorder that responds to is provided. In some embodiments, the at least one histone deacetylase is HDAC-4. In some embodiments, the condition or disorder comprises a neurodegenerative disease. In some embodiments, the condition or disorder is Huntington's disease.

In some embodiments, HDAC-mediated conditions or disorders include the pathology of neurodegeneration. Thus, in a subject in need of such treatment, a method of treating a pathological condition of neurodegeneration mediated by HDAC, wherein a therapeutically effective amount of at least one compound described herein or Methods are also provided that include administering the pharmaceutically acceptable salt thereof.

In some embodiments, the pathophysiology of neurodegeneration is Alzheimer's disease, Parkinson's disease, neuronal cell nuclear encapsulation disease (NIID), dentatorubral erythrocytic paleosphere Louis body atrophy (DRPLA), Friedrich's ataxia, Polyglutamine diseases such as Rubinstein-Tevi syndrome and Huntington's disease; spinocerebellar imbalance 1 (SCA1), spinocerebellar imbalance 7 (SCA7), seizures, striatum melanosis, progressive supranuclear palsy, torsional dystonia, spasticity Oblique neck, dyskinesia, familial tremor, Zildra Turret syndrome, diffuse Levy body disease, progressive supranuclear palsy, Pick's disease, primary lateral sclerosis, progressive neuromuscular atrophy, spinocerebellar atrophy Disease, hypertrophic interstitial multiple neuropathy, pigmented retinitis, hereditary optic nerve atrophy, hereditary spastic vs. palsy, Shy-Drager syndrome, Kennedy's disease, protein aggregation-related neurodegeneration, Machad Joseph's disease, spongy Encephalopathy, prion-related diseases, multiple sclerosis (MS), progressive supranuclear palsy (Steel Richardson Orshevski's disease), Hallelfolden-Spats' disease, progressive familial myocronus epilepsy, cerebellar degeneration, Motor neuron disease, Weldnig-Hoffmann disease, Wolfart-Kugelberg-Welander disease, Schalko-Marie-Tus disease, Degerine Sotta disease, Pigmented retinitis, Labor disease, Progressive systemic sclerosis, Dermatitis Selected from mixed connective tissue diseases.

In some embodiments, the pathology of neurodegeneration is an acute or chronic degenerative disease of the eye. Acute or chronic degenerative diseases of the eye include glaucoma, dry age-related yellowing degeneration, pigmented retinitis and other types of genetically degenerative retinal disease, retinal detachment, retinal packer, ischemia affecting the outer retina, Cellular injury associated with diabetic retinopathy and retinal ischemia, injury associated with laser therapy, ocular angiogenesis, diabetic retinopathy, rubeosis irisitis, vasculitis, Hook's heterochromic iris hair-like body inflammation , Vascular neoplasia, corneal neovascularization, retinal ischemia, choriovascular insufficiency, choroidal thrombosis, carotid ischemia, contusive ocular injury, premature infant retinopathy, retinal vein occlusion, proliferative vitreous retinopathy, These include corneal angiogenesis, retinal microangiopathy, and retinal edema.

In some embodiments, HDAC-mediated conditions or disorders are fibrotic diseases such as liver fibrosis, cystic fibrosis, cirrhosis, and fibrous skin diseases such as hyperplastic scars, keloids and dupuytren's disease. Including shrinkage. Thus, in a subject in need of such treatment, a method of treating HDAC-mediated fibrotic disease to the subject in a therapeutically effective amount of at least one compound described herein or pharmaceutically thereof. Methods are also provided that include administering an acceptable salt to the drug.

In some embodiments, HDAC-mediated conditions or disorders include psychiatric disorders such as depression, bipolar disorder and dementia. In some embodiments, the HDAC-mediated condition or disorder comprises depression. Thus, in a subject in need of such treatment, a method of treating an HDAC-mediated psychiatric disorder such as depression, wherein a therapeutically effective amount of at least one of the therapeutically effective amounts described herein. Methods are also provided that include administering the compound or a pharmaceutically acceptable salt thereof. In some embodiments, depression is selected from major depressive disorder and bipolar disorder.

In some embodiments, HDAC-mediated conditions or disorders include anxiety. Thus, in a subject in need of such treatment, a method of treating HDAC-mediated anxiety, to the subject, a therapeutically effective amount of at least one compound described herein or a pharmacy thereof. Methods are also provided that include administering a pharmaceutically acceptable salt.

In some embodiments, HDAC-mediated conditions or disorders include schizophrenia. Thus, in a subject in need of such treatment, a method of treating HDAC-mediated schizophrenia, to the subject, a therapeutically effective amount of at least one compound described herein or the like thereof. Methods are also provided that include administering a pharmaceutically acceptable salt.

In some embodiments, HDAC-mediated conditions or disorders include motor neuron disease, muscular atrophy / muscle wasting disorder or amyotrophic lateral sclerosis (ALS). Therefore, in a subject in need of such treatment, a method of treating motor neuron disease, muscular atrophy / muscle wasting disorder or amyotrophic lateral sclerosis (ALS) mediated by HDAC, said subject. Also provided is a method comprising administering a therapeutically effective amount of at least one of the compounds described herein or a pharmaceutically acceptable salt thereof.

In some embodiments, HDAC-mediated conditions or disorders include cardiovascular conditions. Thus, in a subject in need of such treatment, a method of treating an HDAC-mediated cardiovascular condition to which a therapeutically effective amount of at least one compound described herein or Methods are also provided that include administering the pharmaceutically acceptable salt thereof. In some embodiments, the cardiovascular condition is selected from cardiomyopathy, cardiac hypertrophy, myocardial ischemia, heart failure, cardiac restenosis and arteriosclerosis.

In some embodiments, HDAC-mediated conditions or disorders include cancer. Thus, in a subject in need of such treatment, a method of treating HDAC-mediated cancer to the subject in a therapeutically effective amount of at least one compound described herein or pharmaceuticals thereof. Methods are also provided that include administering an acceptable salt to the drug. In some embodiments, the cancers are lymphoma, pancreatic cancer, colorectal cancer, hepatocellular carcinoma, Waldenstreme macroglobulinemia, hormone refractory cancer of the prostate, and leukemia, breast cancer, lung cancer. , Ovarian cancer, prostate cancer, head and neck cancer, kidney cancer, gastric cancer, brain cancer, B-cell lymphoma, peripheral T-cell lymphoma, and cutaneous T-cell lymphoma. In some further embodiments, the cancer is selected from the following cancer types: Heart: Sarcoma (angisarcoma, fibrosarcoma, rhombic myoma, liposarcoma), mucinoma, rhombic myoma, fibroma, lipoma and malformation; Lung: bronchial carcinoma (scaly cells, undifferentiated small cells, undifferentiated) Differentiated large cells, adenocarcinoma), alveolar (fine bronchial) cancer, bronchial adenoma, sarcoma, lymphoma, cartilage tumor, mesenteric tumor; gastrointestinal adenomas: esophagus (squamous epithelial cancer, adenocarcinoma, smooth muscle tumor) , Lymphoma), stomach (canceroma, lymphoma, smooth muscle tumor), pancreas (tube adenocarcinoma, insulinoma, glucagonoma, gastrinoma, cartinoid tumor, bipoma), small intestine (adenocarcinoma, lymphoma, cartinoid tumor, caposarcoma, smooth myoma, blood vessel) Tumors, lipomas, neurofibromas, fibromasas), colons (adenocarcinomas, glandular tubular adenomas, chorionic villous adenomas, erroneous tumors, smooth sarcomas); , Lymphoma, leukemia), bladder and urinary tract (flat epithelial carcinoma, transitional epithelial carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, malformation, fetal cancer, malformation, choriocarcinoma, sarcoma, interstitial Cell carcinoma, fibroma, fibroadenoma, adenomas, lipoma); Liver: liver cancer, bile duct sarcoma, hepatoblastoma, angiosarcoma, hepatocellular adenomas, hemangiomas; bone: osteogenic sarcoma (bone) Sarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing sarcoma, malignant lymphoma (fine sarcoma), multiple myeloma, malignant giant cell tumor spondyloma, osteochoron floma (osteochondral sarcoma) , Beni chondroma, chondromacytoma, chondrody mucin fibroma, osteoarthritis and giant cell tumor; Nervous system: skull (sarcoma, hemangiomas, sarcoma, yellow tumor, osteoarthritis), mening membrane ( Meneloma, sarcoma sarcoma, glioma), brain (stellar sarcoma, medullary blastoma, glioma, coat tumor, germ cell tumor {pine fruit sarcoma}, polymorphic glioma, poverty Pulmonary glaucoma, Schwan celloma, retinal blastoma, congenital tumor), spinal cord neurofibroma, meningeal tumor, glioma, sarcoma); Gynecology: uterus (endometrial carcinoma), neck (child) Miya cervical sarcoma, pretumor cervical dysplasia), ovary (ovarian sarcoma [serosal cystal sarcoma, mucinous cystal sarcoma, unclassified sarcoma], granule sarcoma, Sertri-Leidich sarcoma, undifferentiated Embryonic cell tumor, malignant malforma), genital area (flat epithelial cancer, intraepithelial cancer, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous sarcoma, vesicle sarcoma (fetal horizontal sarcoma) Tumors), ovaries (sarcomas); hematological cancers: blood (myeloid leukemia [acute and chronic], acute lymphocytic leukemia, chronic lymphocytic leukemia, myeloproliferative disorders, multiple myeloma, myelodystrophy Syndrome), Hodgkin's disease, non-Hodgkin's sarcoma [malignant sarcoma]; Skin: Malignant melanoma, basal cell carcinoma, squamous cell carcinoma, capsicum sarcoma, dysplastic nevus, lipoma, hemangiomas, cutaneous fibroma, keloids, psoriasis; and adrenal: neuroblastoma. Also provided is a method of sensitizing a tumor to radiation therapy by administering the compound in accordance with the present disclosure before, during or after irradiation of the tumor for treating cancer.

In some embodiments, HDAC-mediated conditions or disorders include conditions or disorders that can be treated by immune modulation. Accordingly, in a subject in need of such treatment, a method of treating a condition or disorder mediated by HDAC that is treatable by immunomodulation, wherein a therapeutically effective amount of the subject is described herein. Methods are also provided that include administering at least one compound or a pharmaceutically acceptable salt thereof. In some embodiments, conditions or disorders treatable by immunomodulation include asthma, irritable bowel syndrome, Crohn's disease, ulcerative colitis, enteromotor disorders, hypertension, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis. , Transplant vs. host disease, psoriasis, spondyloarthropathies, inflammatory colon disease, alcoholic hepatitis, Schegren's syndrome, tonic spondylitis, membranous glomerulopathies, disc-derived pain, systemic erythematosus, allergic bowel disease, ceriac Diseases, bronchitis, cystic fibrosis, rheumatoid spondylitis, osteoarthritis, vasculitis, irisitis and conjunctivitis, ischemic bowel disease, psoriasis, eczema, dermatitis, septic arthritis, gout, pseudogout, juvenile Rheumatoid arthritis, Still's disease, Henoch-Schoenlein purpura, psoriatic arthritis, muscle pain, reactive arthritis (Reiter's syndrome), hemochromatosis, Wegener's granulomatosis, familial Mediterranean fever (FMF), HBDS (globulin hyperemia) D and periodic fever syndrome), TROPS (TNF-alpha receptor-related periodic fever syndrome), chronic obstructive pulmonary disease, neonatal-onset multi-organ inflammatory disease (NOMID), periodic syndrome associated with cryopyrin (CAPS) ) And familial affliction autoinflammatory syndrome (FCAS).

In some embodiments, HDAC-mediated conditions or disorders include allergic diseases. Accordingly, in a subject in need of such treatment, a method of treating an allergic disease mediated by HDAC, wherein a therapeutically effective amount of at least one of the compounds described herein or the like thereof. Methods are also provided that include administering a pharmaceutically acceptable salt. Allergic diseases include respiratory allergic diseases such as allergic rhinitis, hypersensitivity pneumonitis, hypersensitivity pneumonitis, eosinophilic pneumonia, Refrel syndrome, chronic eosinophilic pneumonia, delayed hypersensitivity reaction, and interstitial lung disease. Diseases (ILD), idiopathic pulmonary fibrosis, polymyositis, dermatomyositis, systemic anaphylaxis, drug allergies (eg, to penicillin or cephalosporin) and insect sting allergies are, but are not limited to.

In some embodiments, the condition or disorder mediated by HDAC is an infection, such as a fungal infection, a bacterial infection, a viral infection and a protozoan infection, such as malaria, giardiasis, leishmaniasis, Chagas disease. , Includes diarrhea, toxoplasmosis and coxiardiasis. In some embodiments, HDAC-mediated conditions or disorders include malaria. Thus, in a subject in need of such treatment, a method of treating an HDAC-mediated infection, such as malaria, to which therapeutically effective amount of at least one compound described herein. Alternatively, methods are also provided that include administering the pharmaceutically acceptable salt thereof.

In some embodiments, HDAC-mediated conditions or disorders include autism or Rett syndrome. Thus, in a subject in need of such treatment, a method of treating HDAC-mediated autism or Rett syndrome, wherein a therapeutically effective amount of at least one of the therapeutically effective amounts described herein. Methods are also provided that include administering the compound or a pharmaceutically acceptable salt thereof.

In some embodiments, HDAC-mediated conditions or disorders include blood disorders such as thalassemia, anemia and sickle cell anemia. Accordingly, in a subject in need of such treatment, a method of treating an HDAC-mediated hematological disorder, wherein a therapeutically effective amount of at least one compound described herein or a pharmacy thereof. Methods are also provided that include administering a pharmaceutically acceptable salt.

In some embodiments, HDAC-mediated conditions or disorders include metabolic disorders such as prediabetes or diabetes (type I or type II). Thus, in a subject in need of such treatment, a method of treating an HDAC-mediated metabolic disorder, such as prediabetes or diabetes (type I or type II), to the subject in a therapeutically effective amount. Methods are also provided that include administering at least one of the compounds described herein or a pharmaceutically acceptable salt thereof.

In some embodiments, HDAC-mediated conditions or disorders include disorders that may also be treated by progenitor / stem cell-based therapy, eg, diabetes-related disorders (organ failure, liver cirrhosis and hepatitis); Central nervous system (CNS) disorders associated with dysregulation of brain progenitor cells (eg, post-traumatic stress disorders (PTSD)); tumors (eg, retinoblastoma); disorders affecting progenitor cells of oligodendrogliocytes (Eg stellate cell tumors and epithelial cell tumors); Multiple sclerosis; Demyelinating diseases such as white dystrophy; Neurological disorders with white deficiency; and cerebellar disorders such as ataxia; and olfactory progenitor disorders (eg olfactory sensation) State). Thus, in a subject in need of such treatment, a method of treating a disorder mediated by HDAC, wherein a therapeutically effective amount of at least one of the compounds described herein or pharmaceutically thereof. Also provided are methods that include administering tolerable salts either before, during, or after treatment with progenitor / stem cell based therapy.

In some embodiments, HDAC-mediated conditions or disorders include disorders associated with the proliferation of epithelial cells and mesenchymal cells (eg, tumor, wound healing and surgery). Accordingly, in a subject in need of such treatment, a method of treating an HDAC-mediated disorder associated with proliferation of epithelial cells and mesenchymal cells, wherein a therapeutically effective amount of the subject is described. Methods are also provided that include administering at least one of the compounds described in the book or a pharmaceutically acceptable salt thereof.

In some embodiments, the condition or disorder mediated by HDAC is a disorder associated with the proliferation of bone precursors (eg, osteoblasts and osteoblasts), a disorder associated with hair and epithelial precursors (eg,). Includes disorders associated with hair loss, cutaneous tumors, skin regeneration, burns and cosmetic surgery), as well as disorders associated with bone loss during menopause; therefore, in subjects in need of such treatment, HDAC A method of treating disorders mediated by bone progenitor proliferation, hair and epithelial progenitor-related disorders, or bone loss-related disorders, the therapeutically effective amount for the subject. Also provided are methods comprising administering at least one of the compounds described herein or a pharmaceutically acceptable salt thereof.

In some embodiments, the condition or disorder mediated by the HDAC is a viral disorder that makes the blood cells sensitive to other treatments after HDAC inhibition, followed by a therapeutically effective amount of the subject. Administer at least one of the compounds described herein or a pharmaceutically acceptable salt thereof. Thus, by HDAC in subjects in need of such treatment, including the step of administering to the subject a therapeutically effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof. Methods of treating mediated viral disorders (blood cells are sensitized to other treatments after HDAC inhibition) are also provided.

In some embodiments, the condition or disorder mediated by HDAC is an immune disorder, which is a therapeutically effective amount of at least one compound described herein or pharmaceutically acceptable thereof to the subject. The salts to be administered may be co-treated with TNFα or other immunomodulators. Therefore, the step of administering to a subject a therapeutically effective amount of at least one compound described herein or a pharmaceutically acceptable salt thereof before, during or after treatment with TNFα or another immunomodulator. Also provided are methods of treating HDAC-mediated immunodeficiency in subjects in need of such treatment, including.

In some embodiments, HDAC-mediated conditions or disorders include graft rejection or transplant rejection. Accordingly, in a subject in need of such treatment, a method of treating an HDAC-mediated graft rejection or disorder associated with the graft rejection, wherein a therapeutically effective amount of the subject is described herein. Methods are also provided that include administering at least one compound or a pharmaceutically acceptable salt thereof.

In some embodiments, HDAC-mediated conditions or disorders include blood pressure disorders associated with the regulation of nitric oxide (NO) (eg, hypertension, erectile disorders, asthma, and ocular disorders that are glaucoma). Thus, in a subject in need of such treatment, a method of treating an HDAC-mediated regulation of nitric oxide (NO) -related blood pressure disorders, wherein a therapeutically effective amount is given herein. Methods are also provided that include administering at least one of the listed compounds or pharmaceutically acceptable salts thereof. In some embodiments, the condition or disorder is cardiac hypertrophic disorder. Accordingly, in a subject in need of such treatment, a method of treating an HDAC-mediated cardiohypertrophic disorder, wherein a therapeutically effective amount of at least one compound described herein or Methods are also provided that include administering the pharmaceutically acceptable salt thereof.

A method of treatment in which at least one compound described herein or a pharmaceutically acceptable salt thereof is the only active agent conferred on the subject, and at least one described herein herein. Also provided is a therapeutic method in which a compound of a species or a pharmaceutically acceptable salt thereof is imparted to the subject in combination with one or more additional active agents.

In general, the compounds described herein or pharmaceutically acceptable salts thereof are administered in therapeutically effective amounts by any of the acceptable methods of administration for agents that serve similar utility. Will be. The actual amount of a compound, the active ingredient, will depend on a number of factors, such as the severity of the disease to be treated, the age and relative health of the subject, the efficacy of the compound used, the efficacy of the compound. Routes and forms, and other factors well known to those of skill in the art. The drug can be administered at least once daily, eg once or twice daily.

In some embodiments, the compounds described herein or salts thereof are administered as pharmaceutical compositions. Thus, a pharmaceutical composition comprising at least one pharmaceutically acceptable vehicle selected from carriers, adjuvants and excipients, as well as at least one compound described herein or a pharmaceutically acceptable salt thereof. Is provided. The compounds of the present disclosure can be formulated into pharmaceutical compositions using techniques well known to those of skill in the art.

Pharmaceutically acceptable vehicles must be sufficiently pure and sufficiently low in toxicity in order to make them suitable for administration to the animal being treated. The vehicle can be inactive, or it can have medicinal benefits. The amount of vehicle utilized in conjunction with the compound or its pharmaceutically acceptable salt provides a practical amount of material for administration of the compound or its pharmaceutically acceptable salt per unit dose. Sufficient for

Examples of pharmaceutically acceptable carriers or components thereof are sugars such as lactose, glucose and sucrose; starch such as corn starch and potato starch; cellulose and derivatives thereof such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; powdered traganth; malt. Gelatin; talc; solid lubricating oils such as stearic acid and magnesium stearate; calcium sulfate; synthetic oils; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; polyols such as propylene glycol, glycerin, sorbitol, mannitol And polyethylene glycol; alginic acid; phosphate buffer solution; emulsifiers such as TWEEN®; wetting agents such as sodium lauryl sulfate; colorants; fragrances; tableting agents; stabilizers; antioxidants; preservatives; pyrogens Water not contained; isotonic saline; and phosphate buffer solution.

An optional active agent may be included in the pharmaceutical composition, which does not substantially interfere with the activity of the compounds described herein or their pharmaceutically acceptable salts.

An effective concentration of at least one of the compounds described herein or a pharmaceutically acceptable salt thereof is mixed with a suitable, pharmaceutically acceptable vehicle. Here, in an example in which the compound or a pharmaceutically acceptable salt thereof exhibits insufficient solubility, a method for dissolving the compound may be used. Such methods are known to those of skill in the art and can be used in co-solvents such as dimethyl sulfoxide (DMSO), surfactants such as TWEEN®, or in aqueous sodium bicarbonate. Including, but not limited to, dissolution of.

Upon mixing or addition of the compounds described herein or pharmaceutically acceptable salts thereof, the resulting mixture may be a solution, suspension, emulsion or the like. The form of the resulting mixture depends on several factors, including the intended method of administration and the solubility of the compound or its pharmaceutically acceptable salt in the vehicle of choice. Concentrations effective enough to ameliorate the signs of the disease to be treated may be determined empirically.

The compounds described herein or pharmaceutically acceptable salts thereof are taken orally, locally, parenterally, intravenously, by intramuscular injection, inhaled or sprayed, sublingually, via the lingual. It may be administered by skin, by oral administration, then by rectum, as an eye drop solution, or by other means in a dose-based formulation.

The pharmaceutical composition may be formulated for oral use, such as tablets, lozenges, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or elixirs. Pharmaceutical compositions intended for oral use may be prepared according to any method known to those of skill in the art for the production of pharmaceutical compositions, such compositions being pharmaceutically concise and tasty. One or more agents, such as sweeteners, air fresheners, colorants and preservatives, may be included to provide the product. In some embodiments, the oral pharmaceutical composition contains 0.1-99% of at least one of the compounds described herein or a pharmaceutically acceptable salt thereof. In some embodiments, the oral pharmaceutical composition contains at least 5% (% by weight) of at least one of the compounds described herein or a pharmaceutically acceptable salt thereof. In some embodiments, it contains 25-50%, or 5-75%, at least one of the compounds described herein or a pharmaceutically acceptable salt thereof.

Pharmaceutical compositions administered orally also include liquid solutions, emulsions, suspensions, powders, granules, elixirs, tinctures, syrups and the like. Pharmaceutically acceptable carriers suitable for the preparation of such compositions are well known in the art. Oral pharmaceutical compositions may contain preservatives, air fresheners, sweeteners such as sucrose or saccharin, taste masking agents and colorants.

Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. The syrup and elixir may be formulated with sweeteners such as glycerol, propylene glycol, sorbitol or sucrose. Such pharmaceutical compositions may also contain palliatives.

The compounds described herein or pharmaceutically acceptable salts thereof may be incorporated into oral liquid products such as aqueous or oily suspensions, solutions, emulsions, syrups or elixirs. In addition, pharmaceutical compositions containing the compounds described herein or pharmaceutically acceptable salts thereof may be presented as a dry product for composition with water or other suitable vehicle prior to use. .. Such liquid products include prior art additives such as suspending agents (eg sorbitol syrup, methylcellulose, glucose / sugar, syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, gels of aluminum stearate and hydrogenated edibles. Fats), emulsifiers (eg lecithin, sorbitol monooleate or acacia), non-aqueous vehicles can be included, these are edible oils (eg almond oil, fractionated coconut oil, silyl esters, propylene glycol). And ethyl alcohol), and preservatives (eg, methyl or propyl p-hydroxybenzoic acid and sorbitol).

For suspensions, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, Avicel® RC-591, tragacant and sodium alginate, and typical wetting agents include lecithin and polysorbate 80. Examples of, and typical preservatives, are methylparaben and sodium benzoate.

Aqueous suspensions contain the active material in an additive mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents such as sodium carboxymethyl cellulose, methyl cellulose, hydropropyl methyl cellulose, sodium alginate, polyvinylpyrrolidone, tragacant rubber and acacia rubber, and dispersants or wetting agents are naturally occurring phosphatides such as. It may be lecithin, or a condensed product of alkylene oxide with a fatty acid, such as polyoxyethylene stearate, or a condensed product of ethylene oxide with a long-chain fatty alcohol, such as heptadecaethyleneoxycetanol, or ethylene oxide. It may be a condensed product of fatty acid and hexitol, for example a partial ester derived from a polyethylene sorbitol substituent, or a condensed product of ethylene oxide with a fatty acid and hexitol anhydride, for example a partial ester derived from a polyethylene sorbitan substituent. .. The aqueous suspension may also contain one or more preservatives, such as ethyl, or n-propyl p-hydroxybenzoate.

Oily suspensions may be formulated by suspending the active ingredient in vegetable oils, such as in peanut oil, olive oil, sesame oil or coconut oil, or in mineral oils such as liquid paraffin. The oily suspension may contain thickeners such as beeswax, hard paraffin or cetyl alcohol. Sweeteners, such as those identified above, and fragrances may be added to provide a tasty oral product. These pharmaceutical compositions may be preserved by adding antioxidants such as ascorbic acid.

The pharmaceutical composition may also be in the form of an oil-in-water emulsion. The oily phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable suspending agents are naturally occurring rubbers such as acacia rubber or tragacant rubber, naturally occurring phosphatides such as soybeans, lecithin, and esters or partial esters derived from fatty acids and hexitols, anhydrides such as monooleic acid. The sorbitan and the condensed product of the partial ester with ethylene oxide, for example, sorbitan monooleate polyethylene may be used.

Dispersible powders and granules suitable for the preparation of aqueous suspensions by the addition of water provide the active ingredient in an additive mixture with a dispersant or wetting agent, a suspending agent and one or more preservatives. Suitable dispersants or wetting agents and suspending agents are illustrated by those already listed above.

The tablets, as inert diluents, are conventionally pharmaceutically acceptable adjuvants such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, Arginic acid and sucrose; lubricants typically include, for example, magnesium stearate, stearic acid and talc. Lubricants, such as silicon dioxide, can be used to improve the flow properties of the powder mixture. Colorants such as FD & C dyes can be added for appearance. Sweeteners and air fresheners such as aspartame, saccharin, menthol, peppermint and fruit aromas can be useful adjuvants for chewable tablets. Capsules (including time-releasing and sustained-release formulations) typically contain one or more solid diluents disclosed above. The choice of carrier component is often based on secondary considerations such as taste, cost and storage stability.

Such pharmaceutical compositions may also be coated by prior art methods, typically in pH or time-dependent coatings, such as compounds or pharmaceutically acceptable salts thereof, for the desired topical application. It may be coated to be released in the gastrointestinal tract in the vicinity or at various times to prolong the desired action. Such dosage forms typically include, but are not limited to, one or more types of cellulose phthalate acetic acid, polyvinyl acetic acid phthalate, hydroxypropylmethyl phthalate cellulose, ethyl cellulose, Eudragit® coatings, waxes and shelacs.

Pharmaceutical compositions for oral use may also be presented as hard gelatin capsules, where the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules. May be presented, where the active ingredient is mixed with water, or a medium of oil, such as peanut oil, liquid gelatin or olive oil.

The pharmaceutical composition may be in the form of sterile, injectable, aqueous or oily suspension. The suspension may be formulated according to the known techniques of using these suitable dispersants or wetting agents and suspending agents listed above. The sterile injectable product may also be a sterile injectable solution or suspension in a non-toxic, parenterally acceptable vehicle, such as a solution in 1,3-butanediol. Among the acceptable vehicles that may be utilized are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, non-volatile oils have been utilized in the art as solvents or suspending media. For this purpose, any non-irritating non-volatile oil may be utilized, including synthetic mono and diglycerides. In addition, fatty acids such as oleic acid may be useful in the preparation of injectables.

The compounds described herein or pharmaceutically acceptable salts thereof may be administered parenterally in a sterile medium. Parenteral administration includes subcutaneous injection, intravenous, intramuscular, intrathecal injection or infusion techniques. The compounds described herein or pharmaceutically acceptable salts thereof are either suspended or dissolved in the vehicle, depending on the vehicle or concentration used. Advantageously, adjuvants such as local anesthetics, preservatives and buffers can be dissolved in the vehicle. In many pharmaceutical compositions for parenteral administration, the carrier accounts for at least 90% by weight of the total composition. In some embodiments, the carrier for parenteral administration is selected from propylene glycol, ethyl oleate, pyrrolidone, ethanol and sesame oil.

The compounds described herein or pharmaceutically acceptable salts thereof may also be administered in the form of suppositories for rectal administration of the drug. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and is therefore in the rectum. It will melt and release the drug. Such materials include cocoa butter and polyethylene glycol.

The compounds described herein or pharmaceutically acceptable salts thereof are gels, creams and lotions for local or topical administration, eg, for topical administration for the mucous membranes of the skin and the middle of the eye. , And may be formulated in the form for administration to the eye. Topical pharmaceutical compositions may be in any form, including, for example, solutions, creams, ointments, gels, lotions, emulsions, cleansers, moisturizers, sprays, skin patches and the like.

Such solutions may be formulated with a suitable salt at 0.01% to 10% isotonic solution, pH 5-7. The compounds described herein or pharmaceutically acceptable salts thereof can also be formulated for transdermal administration as transdermal patches.

Topical pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt thereof are described in a variety of carrier materials well known in the art, such as water, alcohols, aloe vera gels, allantin. , Glycerin, vitamins A and E oils, mineral oils, propylene glycol, myristyl PPG-2 propionate and the like.

Other materials suitable for use in topical carriers include, for example, softeners, solvents, wetting agents, thickeners and powders. Examples of each of these types of materials, which can be used alone or as a mixture with one or more materials, are as follows.

Typical softeners include stearyl alcohol, glyceryl monolysinolate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, minced oil, cetyl alcohol, isopropyl isostearate, stearic acid, Isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, dimethylpolysiloxane, di-n-butyl sebacate, myristin Isopropyl acid, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, lacquer oil, castor oil, acetylated lanolin alcohol, petroleum, mineral oil, butyl myristate, isostearic acid. , Palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate and myristyl myristate; sprays such as propane, butane, isobutane, dimethyl ether, carbon dioxide and nitrogen phosphite; solvents such as ethyl alcohol, methylene chloride, Isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethylformamide, tetrahydrofuran; wetting agents such as glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, phthal. Dibutyl and gelatin acids; and powders such as choke, talc, fuller soil, kaolin, starch, rubber, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate. , Organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose and ethylene glycol monostearate.

The compounds described herein or pharmaceutically acceptable salts thereof may also be administered topically in the form of liposome delivery systems, such as small monolayer vesicles, large monolayer vesicles, and multilayer vesicles. Liposomes can be formed from various phospholipids such as cholesterol, stearylamine or phosphatidylcholine.

Other pharmaceutical compositions or pharmaceutically acceptable salts thereof useful for achieving systemic delivery of the compound include sublingual, cheek and nasal dosage forms. Such pharmaceutical compositions typically include soluble filler substances such as sucrose, sorbitol and mannitol, and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Lubricants, lubricants, sweeteners, colorants, antioxidants and fragrances disclosed above may also be included.

The pharmaceutical composition for inhalation can typically be provided in the form of a solution, suspension or emulsion, which uses a dry powder or a prior art spray (eg, dichlorodifluoromethane or trichlorofluoromethane). It can be administered in the form of an aerosol.

The pharmaceutical composition may also optionally contain an activator. The activator may be selected from a wide variety of molecules that function or are independent of different methods to promote the therapeutic effect of the compounds described herein or their pharmaceutically acceptable salts. .. Specific classes of activators include skin penetration promoters and absorption promoters.

The pharmaceutical composition may also be selected from a wide variety of molecules capable of functioning to enhance the therapeutic effect of at least one compound described herein or a pharmaceutically acceptable salt thereof in different ways. Additional active agents may also be included. These optional other active agents, when present, are typically utilized in pharmaceutical compositions at levels ranging from 0.01% to 15%. In some embodiments, it accounts for 0.1% to 10% by weight of the composition. In other embodiments, it accounts for 0.5% to 5% by weight of the composition.

Packaged pharmaceutical compositions are also provided. Such packaged compositions include pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, and a subject (typically a human patient) for treatment. Includes instructions for using the composition to do so. In some embodiments, the instructions are for using the pharmaceutical composition to treat a subject suffering from an HDAC-mediated condition or disorder. The packaged pharmaceutical composition can include providing prescribing information, for example, to a patient or healthcare provider, or as a label in the packaged pharmaceutical composition. The prescribing information may include, for example, efficacy, dosage and administration, contraindications and adverse reaction information related to the pharmaceutical composition.

In all of the above, the compound or a pharmaceutically acceptable salt thereof can be administered alone, as a mixture or in combination with other active agents.

The methods described herein include a method of treating Huntington's disease, which comprises treating the memory and / or cognitive impairment associated with Huntington's disease, the method of which is directed to a subject simultaneously or continuously. , At least one compound described herein or a pharmaceutically acceptable salt thereof, as well as amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoroxetine, sertralin, tetrabenazine, haloperidol, chlorpromazine, thioridazine, sulfride, kethiapine, clozapine. And, but not limited to, lisperidone, which comprises administering one or more additional agents used in the treatment of Huntington's disease. In methods using co-administration, the agents can be present in the concomitant composition or can be administered separately. As a result, at least one of the compounds described herein or a pharmaceutically acceptable salt thereof, as well as amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoroxetine, setraline, terabenazine, haloperidol, chlorpromazine, thioridazine, sulfride, kethiapine. , Crozapine and risperidone, but not limited to, pharmaceutical compositions containing one or more additional pharmaceuticals used in the treatment of Huntington's disease are also provided. Similarly, at least one of the compounds described herein or a pharmaceutically acceptable salt thereof, as well as amitriptyline, imipramine, desipramine, nortriptyline, paroxetine, fluoroxetine, setraline, terabenazine, haloperidol, chlorpromazine, thioridazine, sulfride, kethiapine. , Crozapine and lisperidol, but also packaged pharmaceutical compositions containing pharmaceutical compositions containing another composition comprising one or more additional pharmaceuticals used in the treatment of Huntington's disease. Provided.

Also, a method of treatment for Alzheimer's disease, which comprises treating the memory and / or cognitive impairment associated with Alzheimer's disease, which method is described herein simultaneously or continuously. At least one of the listed compounds or a pharmaceutically acceptable salt thereof, as well as Reminyl®, Cognex®, Aricept®, Excelon®, Acatinol®, Neotropin (Registered Trademark) Methods are also provided that include, but are not limited to, administering one or more additional agents used in the treatment of Alzheimer's disease, such as, but not limited to, Eldepril®, estrogen and cryoquinol. In methods using co-administration, the agents can be present in the concomitant composition or can be administered separately. Also, at least one of the compounds described herein or a pharmaceutically acceptable salt thereof, as well as Reminyl®, Cognex®, Aricept®, Excelon®, Acatinol (registered trademark). Also provided are pharmaceutical compositions containing one or more additional pharmaceuticals used in the treatment of Alzheimer's disease, including but not limited to Registered Trademarks), Neotropin®, Eldepril®, Estrogen and Clioquinol. Will be done. Similarly, at least one of the compounds described herein or a pharmaceutically acceptable salt thereof, as well as Reminyl®, Cognex®, Aricept®, Excelon®, Acatinol. Another composition containing one or more additional pharmaceuticals used in the treatment of Alzheimer's disease, including but not limited to (registered trademark), neotropin (trademark), eldepril (registered trademark), estrogen and cryoquinol. A packaged pharmaceutical composition containing a pharmaceutical composition comprising

Also, a method of treating cancer, simultaneously or continuously to a subject, at least one compound described herein or a pharmaceutically acceptable salt thereof, and the following antitumor agents. Methods are also provided that include, but are not limited to, administering one or more additional agents used in the treatment of cancer:
(i) Other cell cycle inhibitors, those that act by the same or different mechanisms as defined herein, such as cyclin-dependent kinase (CDK) inhibitors, specifically CDK2 inhibitors.
(ii) Cell division inhibitors such as anti-estrogen (eg tamoxyphene, tremiphen, laroxyphene, droloxyphene, idoxyphene), progestogen (eg meguestrol acetate), aromatase inhibitors (eg anastrosol, letrazole, borazole, etc.) Exemestane), anti-progestogen, anti-androgen (eg flutamide, niltamide, bicartamide, cyproterone acetate), LHRH agonists and antagonists (eg gocerelin acetate, ruprolide), inhibitors of testosterone 5α-dihydroreductase (eg finasteride), anti-infiltrators (Metalloproteinase inhibitors such as marimastat, and inhibitors of urokinase plus minogen activator receptor function), and growth factor function inhibitors (such growth factors include, for example, vascular endothelial growth factor, epithelium). Growth factors, platelet-derived growth factors and hepatocellular growth factors are included, and such inhibitors include growth factor antibodies, growth factor receptor antibodies, tyrosine kinase inhibitors and serine / threonine kinase inhibitors).
(iii) Antiproliferative / antineoplastic agents and their concomitant medications, those used in medical oncology, such as metabolic antagonists (eg, folic acid metabolic antagonists such as metotoposide, 5-fluorouracil, purine and adenosine-like. Body, fluoropyrimidines such as cytosine arabinoside), antitumor antibiotics (eg doxorubicin, daunomycin, epirubicin and idarubicin, mitomycin C, dactinomycin, anthracyclines such as mitramycin); platinum derivatives (eg cisplatin, carboplatin) ); Alkylating agents (eg, nitrogen mustard, melfaran, chlorambucil, busulfan, cyclophosphamide, ifofamide, nitrosourea, thiotepa); Taxoids such as); topoisomerase inhibitors (eg epipodophylrotoxins such as etoposide and teniposide, amsacline, topotecan)
(iv) Anti-angiogenic agents, those that act by a mechanism different from that previously described herein (eg, receptor tyrosine kinases such as Tie-2, inhibitors of integrin αvβ ₃ function, angiostatins, Razoxin, thalidomide), and those containing vascular targeting agents, as well as
(v) Differentiators (eg retinoic acid and vitamin D).

In the method using co-administration, the agents can be present in the combination composition or can be administered separately. Also provided are pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, and one or more antitumor agents described herein. Similarly, a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt thereof, and another composition comprising one or more antitumor agents described herein. A packaged pharmaceutical composition containing the same is also provided. When used in combination with one or more additional medicinal products, the compounds described herein may be administered at the same time as or thereafter before the additional medicinal product is administered.

In some embodiments, the compounds described herein or pharmaceutically acceptable salts thereof are administered in conjunction with surgery or radiation therapy and are optionally used in the treatment of cancer. It is administered in combination with the above additional drugs.

The doses of the compounds described herein, among other considerations, are the specific syndrome to be treated, the severity of the symptoms, the route of administration, the frequency of dosing intervals, the specific compound utilized, Due to a variety of factors, including efficacy, toxicological profile, pharmacokinetic profile of compounds, and the presence of any adverse side effects.

The compounds described herein or pharmaceutically acceptable salts thereof are typically administered to HDAC inhibitors at conventional levels and methods. For example, a compound or pharmaceutically acceptable salt thereof, in a single or multiple doses, is generally 0.001 to 100 mg / kg / day, such as 0.01 to 100 mg / kg / day, such as 0.1 to 70 mg / kg / day. For example, it can be administered by oral administration at dose levels of 0.5-10 mg / kg / day. Unit dosage forms can generally contain 0.01-1000 mg of at least one compound described herein or a pharmaceutically acceptable salt thereof, eg 0.1-50 mg described herein. It can contain at least one compound or a pharmaceutically acceptable salt thereof. For intravenous administration, the compound is administered in single or multiple doses, eg, at a dose level of 0.001-50 mg / kg / day, eg 0.001-10 mg / kg / day, eg 0.01-1 mg / kg / day. Can be administered. The unit dosage form can contain, for example, 0.1-10 mg of at least one of the compounds described herein or a pharmaceutically acceptable salt thereof.

Labeled forms of the compounds described herein or pharmaceutically acceptable salts thereof identify and / or obtain the compounds described herein having the ability to modulate the activity of HDCA. Can be used as a diagnostic agent for. The compounds described herein or pharmaceutically acceptable salts thereof may be further used to validate, optimize and standardize bioassays.

As used herein, "labeled" means a signal in which the compound can be detected either directly or indirectly, such as a radioisotope, a fluorescent tag, an enzyme, an antibody, a particle such as a magnetic particle, a chemically luminescent tag or a specific. It means that it is labeled with a label that imparts a specific binding molecule or the like. Specific binding molecules include pairs of biotin and streptavidin, digoxin and antidigoxin, and the like. For specific binding members, complementary members are usually labeled with a molecule that imparts detection according to known procedures, as outlined above. The label can directly or indirectly impart a detectable signal.

The present disclosure includes all isotopes of atoms generated in the compounds and their pharmaceutically acceptable salts described herein. Isotopes include atoms with the same atomic number but different mass numbers. The disclosure also includes any combination of one or more atoms in the compounds described herein and their pharmaceutically acceptable salts, which are replaced by atoms having the same atomic number but different mass numbers. Is done. One such example is an atom that is the most naturally abundant isotope, eg, ¹ H or ¹² C, to a different atom that is not the most naturally abundant isotope, eg, ² H or ³ H. Found in one of the compounds and pharmaceutically acceptable salts thereof described herein, replaced by ( ¹ H replacement) or ¹¹ C, ¹³ C, or ¹² C ( ¹² C replacement). Is done. Compounds with such substitutions are commonly referred to as being labeled with isotopes. Isotopic labeling of compounds and their pharmaceutically acceptable salts described herein can be achieved using any one of a variety of different synthetic methods known to those of skill in the art. It is readily appreciated that the synthetic methods and reagents available for performing such isotopic labeling will be understood. Common examples, and not limited to, hydrogen isotopes include ² H (deuterium) and ³ H (tritium). Carbon isotopes include ¹¹ C, ¹³ C, and ¹⁴ C. Nitrogen isotopes include ¹³ N and ¹⁵ N. Oxygen isotopes include ¹⁵ O, ¹⁷ O, and ¹⁸ O. Fluorine isotopes include ¹⁸ F. Sulfur isotopes include ³⁵ S. Chlorine isotopes include ³⁶ Cl. Bromine isotopes include ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, and ⁸² Br. Iodine isotopes include ¹²³ I, ¹²⁴ I, ¹²⁵ I, and ¹³¹ I. Also provided are pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, which disrupt the naturally occurring distribution of isotopes in the pharmaceutical compositions. Also provided are pharmaceutical compositions comprising the compounds described herein or pharmaceutically acceptable salts thereof, fortified at one or more positions having isotopes other than the most naturally abundant isotopes. Will be done. Methods are readily available to measure the disturbance or enhancement of such isotopes, for example mass spectrometry, and in the case of isotopes that are radioactive isotopes, additional methods are available. For example, a radio wave detector used in connection with HPLC or gas chromatography (GC). The compounds labeled with some isotopes and their pharmaceutically acceptable salts described herein are useful in compound and / or substrate tissue distribution assays. In some embodiments, radionuclide ³ H and / or ¹⁴ C isotopes are useful for these tests. In addition, replacement with heavier isotopes, such as deuterium (ie, ² H), results in some therapeutic benefits resulting from better metabolic stability (eg, increased in vivo half-life or dose). It can result in a reduction in requirements) and is therefore preferable under some circumstances. The isotope-labeled compounds and their pharmaceutically acceptable salts described herein are described below by replacing the isotope-labeled reagent with an isotope-unlabeled reagent. It can generally be prepared by the following procedure similar to that disclosed in the examples. Moreover, all of the atoms shown in the compounds and their pharmaceutically acceptable salts described herein are the most commonly present or rare radioactive or non-radioactive isotopes of such atoms. It should be understood that it can be a body.

In carrying out the procedures of the methods described herein, of course, no reference is intended to limit reference to specific buffers, media, reagents, cells, culture conditions, etc. It shall be understood that the matter is construed to include all relevant material that one of ordinary skill in the art would find interesting or valuable in the particular context in which it is presented. It is often possible to achieve similar results, for example, by replacing one buffer system or medium with another, if not yet identical. Such so that one of ordinary skill in the art can use the methods and procedures disclosed herein to make a replacement that will best serve the purposes of those skilled in the art without undue experimentation. You will have sufficient knowledge of systems and methodologies.

[Example]
The compounds described herein or pharmaceutically acceptable salts, compositions and methods thereof are further described by the following non-limiting examples.

As used herein, the following abbreviations have the following meanings: If an abbreviation is not defined, it has its generally accepted meaning.

Abbreviation
AcOH acetic acid
Bn: benzyl
BOC or Boc: tert-butyloxycarbonyl
cPr: cyclopropyl
DCM: Dichloromethane
DIPE: diisopropyl ether
DIPEA: Diisopropylethylamine
DMAP: Dimethylaminopyridine
DMF: Dimethylformamide
DMSO: Dimethyl sulfoxide
EDC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide
eqs: equivalent
ES +: Electrospray cationization
Et ₂ O: Diethyl ether
EtOAc: ethyl acetate
EtOH: Ethanol
FBS fetal bovine serum
h: time
HATU: (1- [bis (dimethylamino) methylene] -1H-1,2,3-triazolo [4,5-b] pyridinium 3-oxide hexafluorophosphate)
HBTU: N, N, N', N'-tetramethyl-O- (1H-benzotriazole-1-yl) uronium hexafluorophosphate
HOPO: 2-Hydroxypyridin-N-oxide
HPLC: High Performance Liquid Chromatography
i-hex: iso-hexane
IPA: iso-propyl alcohol
LCMS: Liquid Chromatography Mass Spectrometry
M: Mass
Me: Methyl
MeCN: Acetonitrile
MeOH: Methanol
min: minutes
Ms: Mesylate
NMR: Nuclear Magnetic Resonance
Pd / C: Carbon-supported palladium
Ph: Phenyl
RT: Retention time
rt: room temperature
SFC: Supercritical Liquid Chromatography
SCX: Strong cation exchange
TFA: Trifluoroacetic acid
TFAA: Trifluoroacetic anhydride
THF: tetrahydrofuran
v / v or V / V: Volume vs. Volume

Compounds were named using Cambridgesoft Chemistry Cartridge (v.9.0.0.182) software.

All reactions, including reagents unstable to air or humidity, were carried out in a nitrogen atmosphere using dry solvents and glassware.
Analysis conditions

General synthesis method

Method A (Amid Coupling)
EDC (351 mg, 1.83 mmol) and HOPO (203 mg, 1.83 mmol) were added to a solution of carboxylic acid (1.50 mmol) in DCM (10 mL) at room temperature. The mixture was stirred for 30 minutes to give a complete solution, then amine (free base or hydrochloride) (1.65 mmol) and DIPEA (1.3 mL, 7.5 mmol) were added and the mixture was stirred at room temperature for 18 h. The mixture was washed with water, passed through a phase separation cartridge and concentrated.

Method B (amide reduction)
Lithium aluminum hydride (1.30 mL, 2.6 mmol, 2.0 M in THF) was added dropwise to a solution of amide (1.30 mmol) in diethyl ether (50 mL) under nitrogen at -15 ° C for 20 minutes. The reaction was maintained at -10 ° C. for 1.5 h and then quenched with water (1.5 mL), 2N NaOH (1 mL) and then water (2 mL). The reaction was warmed to rt, stirred for 30 minutes, then DDL ₄ was added, the reaction was filtered through Celite and washed thoroughly with EtOAc. The filtrate was concentrated and the residue was purified by passing through an SCX cartridge (5 g) and eluting with 0-10% 7M methanol ammonia in DCM.

Method C (Boc removal)
4N HCl in dioxane (0.8 mL, 3.0 mmol) was added dropwise to a solution of amine (0.76 mmol) protected by Boc- under nitrogen at 0 ° C. in DCM (5 mL). The solution was warmed to room temperature, stirred for 1 h and then concentrated.

ステップ1:(R)-2-((tert-ブトキシカルボニル)アミノ)プロピルメタンスルホネート(中間体1)
メタンスルホニルクロリド(7.29mL、94.2mmol)の乾燥DCM(140mL)溶液を、(R)-tert-ブチル(1-ヒドロキシプロパン-2-イル)カルバメート(15g、85.6mmol)及びトリエチルアミン(17.9mL、128.4mmol)のDCM(300mL)溶液に、0℃で1.5hにわたって滴加した。反応物を、0℃で30分間撹拌し、次いでr.tで1h撹拌し、その後、水(300mL)、NaHCO₃(300mL)及び食塩水(200mL)で洗浄した。有機物を、相分離器に通し、減圧下で濃縮して、標題化合物をサーモンピンク色固体として得た(21.5g、99%)。

Step 1: (R) -2-((tert-butoxycarbonyl) amino) propylmethanesulfonate (intermediate 1)
A dry DCM (140 mL) solution of methanesulfonyl chloride (7.29 mL, 94.2 mmol) was added to (R) -tert-butyl (1-hydroxypropan-2-yl) carbamate (15 g, 85.6 mmol) and triethylamine (17.9 mL, 128.4). To a solution of mmol) in DCM (300 mL) was added dropwise at 0 ° C. over 1.5 h. The reaction was stirred at 0 ° C. for 30 minutes, then rt for 1 h and then washed with water (300 mL), LVDS ₃ (300 mL) and saline (200 mL). The organic matter was passed through a phase separator and concentrated under reduced pressure to give the title compound as a salmon pink solid (21.5 g, 99%).

Method D
Amine (7.12 mmol) was added to intermediate 1 (900 mg, 3.56 mmol) and cesium carbonate (3.48 g, 10.7 mmol) in DMF (8 mL) and the mixture was stirred at 65 ° C. for 24 h. The reaction mixture was cooled to room temperature, filtered through Celite and washed with MeOH. The filtrate was concentrated and the residue was purified by passing through an SCX cartridge (5 g) and eluting with 0-10% 7M methanol ammonia in DCM.
(R) -1-((S) -2-Methylpyrrolidine-1-yl) Propane-2-aminedihydrochloride (Intermediate 2)

ステップ1:tert-ブチル((R)-1-((S)-2-メチルピロリジン-1-イル)-1-オキソプロパン-2-イル)カルバメート
(R)-2-((tert-ブトキシカルボニル)アミノ)プロパン酸(1.14g、6.04mmol)及び(S)-2-メチルピロリジン(565mg、6.65mmol)から方法Aに従って、標題化合物を黄色油状物として得、これを、未精製物として次のステップに進行させた。

Step 1: tert-Butyl ((R) -1-((S) -2-methylpyrrolidine-1-yl) -1-oxopropan-2-yl) carbamate
From (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (1.14 g, 6.04 mmol) and (S) -2-methylpyrrolidine (565 mg, 6.65 mmol) according to Method A, the title compound was yellow oil. It was obtained as an unrefined product and proceeded to the next step.

Step 2: tert-Butyl ((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) carbamate
From tert-butyl ((R) -1-((S) -2-methylpyrrolidine-1-yl) -1-oxopropan-2-yl) carbamate (1.55 g, 6.04 mmol) according to Method B, the title compound Obtained as a colorless oil (1.43 g, 97%).

Step 3: (R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-amine dihydrochloride (intermediate 2)
From tert-butyl ((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) carbamate (1.43 g, 5.88 mmol) according to Method C, the title compound as a colorless oil. Obtained (850 mg, 81%).

[Example 1]
(2S) -2-Methyl-1-((R) -2-(3-Methyl-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl ) Pyrrolidine-1-iumformate

ステップ1:(Z)-4-(N'-ヒドロキシカルバムイミドイル)-3-メチル安息香酸
4-シアノ-3-メチル安息香酸(1.00g、6.21mmol)のEtOH(30mL)撹拌溶液に、NH₂OH.HCl(604mg、8.70mmol)及びKOH(1.04g、18.6mmol)を加えた。混合物を、室温で17h撹拌し、次いで、1M HCl_(aq)で中和し、EtOAc(3×25mL)中で抽出した。合わせた有機物を、乾燥し(MgSO₄)、濃縮して、標題化合物を黄色固体として得た(1.3g、108%)。

Step 1: (Z) -4- (N'-Hydroxycarbamimideyl) -3-methylbenzoic acid
NH ₂ OH. HCl (604 mg, 8.70 mmol) and KOH (1.04 g, 18.6 mmol) were added to a stirred solution of 4-cyano-3-methylbenzoic acid (1.00 g, 6.21 mmol) in EtOH (30 mL). The mixture was stirred at room temperature for 17 h, then neutralized with 1M HCl _(aq) and extracted in EtOAc (3 x 25 mL). The combined organics were dried (DDL ₄ ) and concentrated to give the title compound as a yellow solid (1.3 g, 108%).

Step 2: 3-Methyl-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid
TFAA (1.29 mL, 9.32 mmol) was added to a stirred solution of (Z) -4- (N'-hydroxycarbamimideyl) -3-methylbenzoic acid (1.2 g, 6.21 mmol) in THF (30 mL). The mixture was stirred for 3 h and after that period additional TFAA5eqs were added. After a further 2 h of stirring, LCMS showed that the reaction was complete. The mixture was poured into ice-water, acidified to pH 4 with 1M HCl _(aq) and then extracted in EtOAc (3 x 30 mL). The combined organic matter was dried (DDL ₄ ) and concentrated. Purification by flash column chromatography (gradient elution i-hex [+ 3% AcOH] to i-hex: EtOAc [+ 3% AcOH] 4: 1) gave the title compound as an off-white solid. LCMS (ES +) is consistent with target (M + H) ⁺ .

Step 3: (2S) -2-Methyl-1-((R) -2-(3-Methyl-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl)) Benzamide) propyl) pyrrolidine-1-iumformate
Method A from 3-methyl-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (490 mg, 1.80 mmol) and intermediate 2 (386 mg, 2.70 mmol) Follow. Purification by reverse phase chromatography gave the title compound as an orange rubbery substance (65 mg, 9%). LCMS (ES +) 397 (M + H) ⁺ , RT 2.85 minutes (analysis method 1). ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.40 (1H, d, J = 8.3 Hz), 8.17 (1H, s), 8.04 (1H, d, J = 8.2 Hz), 7.92 (1H, s), 7.88 --7.85 (1H, m), 4.19 --4.10 (1H, m), 3.16 --3.10 (1H, m) ), 2.78 --2.67 (1H, m), 2.65 (3H, s), 2.42 --2.33 (1H, m), 2.29 --2.15 (2H, m), 1.93 --1.83 (1H, m), 1.72 --1.62 (2H) , m), 1.36-1.25 (1H, m), 1.19 (3H, d, J = 6.7 Hz), 1.05 (3H, d, J = 6.0 Hz). NH ⁺ is not allowed.

[Example 2]
N-(2- (3-azabicyclo [3.2.1] octane-3-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide

ステップ1:N-(2-ヒドロキシエチル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド
4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)安息香酸(1.5g、5.8mmol)及び2-アミノエタノール(420μL、6.96mmol)から方法Aに従って、標題化合物を白色固体として得た(938mg、54%)。LCMS(ES+)は、標的(M+H)⁺と整合している。

Step 1: N- (2-Hydroxyethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide
From 4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (1.5 g, 5.8 mmol) and 2-aminoethanol (420 μL, 6.96 mmol) according to Method A. The title compound was obtained as a white solid (938 mg, 54%). LCMS (ES +) is consistent with target (M + H) ⁺ .

Step 2: N- (2-oxoethyl) -4-(5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide
In a DCM (50 mL) suspension of N- (2-hydroxyethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide (938 mg, 3.11 mmol). , Death-Martin periodinane (1.98 g, 4.67 mmol) was added. The reaction mixture was stirred at room temperature for 66 h and then quenched with MeOH (15 mL). The mixture was stirred for 15 minutes and then concentrated on silica. Purification by column chromatography (i-hex vs. EtOAc / i-hex (1: 1)) gave the title compound (450 mg, 48%).

Step 3: N-(2-((1R, 5S) -3-azabicyclo [3.2.1] octane-3-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxa Diazol-3-yl) benzamide
DCM: AcOH (10: 1, 4 mL) of N- (2-oxoethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide (87 mg, 0.4 mmol) ) 3-Azabicyclo [3.2.1] octane (70 mg, 0.48 mmol) and PS-cyanoborohydride triethylammonium cyanoborohydride (200 mg, 0.8 mmol) were added to the stirred solution. The reaction was shaken for 4 hours, then filtered under reduced pressure and concentrated. Preparative-purification by HPLC gave the title compound. LCMS (ES +) 395 (M + H) ⁺ , RT 2.75 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.55-8.50 (1H, m,), 8.17 (2H) , d, J = 8.5 Hz), 8.04 (2H, d, J = 8.5 Hz), 3.40-3.35 (2H, m), 2.72 --2.66 (2H, m), 2.46 (2H, dd, J = 6.8, 6.8) Hz), 2.09 --2.03 (4H, m), 1.60 --1.51 (2H, m), 1.50 --1.38 (3H, m), 1.31 (1H, d, J = 10.7 Hz).

[Example 3]
(R) -N- (1- (isoindoline-2-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide

ステップ1:(R)-tert-ブチル(1-(イソインドリン-2-イル)-1-オキソプロパン-2-イル)カルバメート
(R)-2-((tert-ブトキシカルボニル)アミノ)プロパン酸(3.78mmol)及びイソインドリン(4.16mmol)から方法Aに従う。カラムクロマトグラフィー(勾配溶出、i-hex中の0〜100%EtOAc)による精製によって、標題化合物を淡黄色ゴム状物として得(1.01g、87%、60%純粋)、これをさらには精製せずに使用した。

Step 1: (R) -tert-butyl (1- (isoindoline-2-yl) -1-oxopropan-2-yl) carbamate
Follow Method A from (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (3.78 mmol) and isoindoline (4.16 mmol). Purification by column chromatography (gradient elution, 0-100% EtOAc in i-hex) yields the title compound as a pale yellow rubber (1.01 g, 87%, 60% pure), which is further purified. Used without.

Step 2: (R) -tert-butyl (1- (isoindoline-2-yl) propan-2-yl) carbamate
Follow Method B from (R) -tert-butyl (1- (isoindoline-2-yl) -1-oxopropan-2-yl) carbamate (3.78 mmol). The title compound was obtained as a yellow rubbery substance (0.84 g, 80%).

Step 3: (R) -1- (isoindoline-2-yl) propan-2-amine dihydrochloride
Follow Method C from (R) -tert-butyl (1- (isoindoline-2-yl) propan-2-yl) carbamate (3.04 mmol). The title compound was obtained as a dark green foam (655 mg, 86%).

Step 4: (R) -N- (1- (isoindoline-2-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3- Il) Benzamide
(R) -1- (isoindoline-2-yl) propan-2-amine dihydrochloride (2.53 mmol) and 4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) ) Follow Method A from benzoic acid (2.78 mmol). Purification by preparative HPLC gave the title compound as a light brown solid (60 mg, 6%). LCMS (ES +) 417 (M + H) ⁺ , RT 9.72 minutes (analysis method 3); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.50 (1H, d, J = 8.2 Hz), 8.17 (2H, d, J = 8.5 Hz), 8.08 (2H, d, J = 8.5 Hz), 7.25 --7.16 (4H, m), 4.33 --4.24 (1H, m), 3.98 --3.88 (4H, m), 2.89 (1H, dd, J = 7.8, 11.9 Hz), 2.73 (1H, dd, J = 6.4, 11.9 Hz), 1.23 (3H, d, J = 6.7 Hz).

[Example 4]
N-((2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide

ステップ1:3-ベンジル-3-アザビシクロ[3.1.0]ヘキサン
3-ベンジル-3-アザビシクロ[3.1.0]ヘキサン-2,4-ジオン(1.95g、9.69mmol、CAS番号73799-63-0)を、THF(11mL)に懸濁し、窒素雰囲気下で0℃まで冷却した。LiAlH₄(THF中の2M、19.5mL、39.0mmol)を、撹拌しながら数分間にわたって加えた。反応物を加熱還流し、放置して18h撹拌した。次いで、反応物を、水(3mL)、2N NaOH(4mL)、さらに水(8mL)をゆっくり加えながらクエンチした。MgSO₄を加え、混合物を30分間撹拌し、その後セライトで濾過し、EtOAcで洗浄した。溶媒を減圧下で除去して、標題化合物を油性黄色固体として生成した(1.38g、82%)。化合物は、さらには精製せずに次のステップに使用した。

Step 1: 3-Benzyl-3-azabicyclo [3.1.0] hexane
3-Benzyl-3-azabicyclo [3.1.0] hexane-2,4-dione (1.95 g, 9.69 mmol, CAS number 73799-63-0) was suspended in THF (11 mL) at 0 ° C. in a nitrogen atmosphere. Cooled to. LiAlH ₄ (2M in THF, 19.5 mL, 39.0 mmol) was added over several minutes with stirring. The reaction was heated to reflux, left to stand and stirred for 18 hours. The reaction was then quenched with the slow addition of water (3 mL), 2N NaOH (4 mL) and water (8 mL). DDL ₄ was added and the mixture was stirred for 30 minutes, then filtered through Celite and washed with EtOAc. The solvent was removed under reduced pressure to give the title compound as an oily yellow solid (1.38 g, 82%). The compound was used in the next step without further purification.

Step 2: 3-Azabicyclo [3.1.0] Hexane Hydrochloride
3-Benzyl-3-azabicyclo [3.1.0] hexane (1.1 g, 6.35 mmol) was dissolved in methanol (40 mL) and 10% Pd / C (300 mg, 0.282 mmol) was added. The mixture was shaken at room temperature for 18 h under a hydrogen gas atmosphere (2 bar). The reaction mixture was then filtered through Celite, acidified with 4N HCl in dioxane (2.38 mL, 9.53 mmol) and concentrated to produce the title compound as a brown solid (680 mg, 90%), which further comprises. It was used in the next step without purification.

Step 3: tert-Butyl ((2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) -1-oxopropan-2-yl) carbamate
3-Azabicyclo [3.1.0] hexane hydrochloride (670 mg, 5.6 mmol) was dissolved in DMF (15 mL), HATU (2.55 g, 6.70 mmol) and Boc-D-alanine (1.06 g, 5.60 mmol) were added. The mixture was stirred at room temperature for 10 minutes. DIPEA (2.92 mL, 16.8 mmol) is then added and the mixture is left to stir at room temperature for 18 h, then diluted with EtOAc (20 mL), 1M HCl (15 mL), saturated LVDS ₃ (15 mL) and saline (15 mL). ) Was washed. The organic layer was dehydrated with DDL ₄ and filtered, and the filtrate was concentrated to produce a yellow oil. Purification by column chromatography (gradient elution, 60% EtOAc in i-hex vs. i-hex) gave the title compound as a clear oil (380 mg, 27%).

Step 4: tert-Butyl ((2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) carbamate
From tert-butyl ((2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) -1-oxopropan-2-yl) carbamate (380 mg, 1.50 mmol) according to Method B, the title compound. Produced as a yellow oil (290 mg, 80%). The compound was used in the next step without further purification.

Step 5: (2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) propan-2-amine
Follow Method C from tert-butyl ((2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) carbamate (290 mg, 1.20 mmol). The reaction mixture was then concentrated to produce a brown oil, which was purified with an SCX cartridge and eluted with MeOH / DCM (1: 1), then 0.5N NH ₃ in MeOH, and the title compound. Was produced as a yellow oil (110 mg, 65%), which was used in the next step without further purification.

Step 6: N-((2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4 -Oxadiazole-3-yl) benzamide
(2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) propan-2-amine (83 mg, 0.59 mmol) and 4- (5- (trifluoromethyl) -1,2,4- Oxadiazole-3-yl) Follow Method A from benzoic acid (153 mg, 0.59 mmol). Preparative-purification by HPLC gave the title compound as an off-white solid. LCMS (ES +) 381 (M + H) ⁺ , RT 2.61 min (analysis method 1); ¹ H NMR δ (ppm) (400 MHz, CDCl ₃ ) 8.19 (2H, td, J = 1.8, 8.4 Hz), 7.92 (2H, td, J = 1.8, 8.5 Hz), 6.97 (1H, br s), 4.08 (1H, br s), 3.10 (1H, d, J = 8.8 Hz), 3.03 (1H, d, J = 8.8 Hz) Hz), 2.74 (1H, t, J = 10.3 Hz), 2.58 (1H, d, J = 8.4 Hz), 2.52 (1H, dd, J = 5.2, 12.3 Hz), 2.41 (1H, d, J = 8.1) Hz), 1.42 --1.39 (2H, m), 1.31 (3H, d, J = 6.4 Hz), 0.65 (1H, dd, J = 3.9, 8.0 Hz), 0.40 (1H, dt, J = 4.3, 7.7 Hz) ).

[Example 5]
(S) -N- (1-Cyclopropyl-2- (pyrrolidin-1-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide

ステップ1:(S)-tert-ブチル(1-シクロプロピル-2-オキソ-2-(ピロリジン-1-イル)エチル)カルバメート
(S)-2-((tert-ブトキシカルボニル)アミノ)-2-シクロプロピル酢酸(1.0g、4.65mmol)及びピロリジン(0.58mL、6.98mmol)から方法Aに従って、標題化合物を無色油状物として得、これを、さらには精製せずに次のステップに進行させた。

Step 1: (S) -tert-butyl (1-cyclopropyl-2-oxo-2- (pyrrolidin-1-yl) ethyl) carbamate
Obtain the title compound as a colorless oil from (S) -2-((tert-butoxycarbonyl) amino) -2-cyclopropylacetic acid (1.0 g, 4.65 mmol) and pyrrolidine (0.58 mL, 6.98 mmol) according to Method A. , This was taken to the next step without further purification.

Step 2: (S) -tert-butyl (1-cyclopropyl-2- (pyrrolidin-1-yl) ethyl) carbamate
The title compound was obtained from (S) -tert-butyl (1-cyclopropyl-2-oxo-2- (pyrrolidin-1-yl) ethyl) carbamate (1.53 g, 5.7 mmol) according to Method B, further. Used without purification.

Step 3: (S) -1-cyclopropyl-2- (pyrrolidin-1-yl) ethaneamine
Follow Method C from (S) -tert-butyl (1-cyclopropyl-2- (pyrrolidin-1-yl) ethyl) carbamate (920 mg, 3.62 mmol). Free amine was dissolved in the residue obtained after aqueous post-treatment in DCM / MeOH (1: 1, 5 mL) and 7M NH ₃ (1: 1: 0.05) in SCX cartridge (DCM: MeOH: MeOH). It was isolated by passing it through (eluted in). The title compound was obtained as an orange oil (390 mg, 70%).

Step 4: (S) -N- (1-cyclopropyl-2- (pyrrolidin-1-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3- Il) Benzamide
(S) -1-Cyclopropyl-2- (pyrrolidin-1-yl) ethaneamine (134 mg, 0.87 mmol) and 4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) ) Follow Method A from benzoic acid (150 mg, 0.58 mmol). LCMS (ES +) 395 (M + H) ⁺ , RT 2.67 minutes (analysis method 1). ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.42 (1H, d, J = 8.7 Hz), 8.15 (2H, d, J = 8.4 Hz), 8.05 (2H, d, J = 8.5 Hz), 3.71 --3.63 (1H, m), 2.80 (1H, dd, J = 9.1, 12.1 Hz), 2.52 --2.49 ( 3H, m), 2.48-2.40 (2H, m), 1.62 (4H, s), 1.02 --0.93 (1H, m), 0.50 --0.43 (1H, m), 0.36 --0.29 (2H, m), 0.24- 0.17 (1H, m).

[Example 6]
(R) -N- (1-Cyclopropyl-2- (pyrrolidin-1-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide

ステップ1:(R)-tert-ブチル(1-シクロプロピル-2-オキソ-2-(ピロリジン-1-イル)エチル)カルバメート
(R)-2-((tert-ブトキシカルボニル)アミノ)-2-シクロプロピル酢酸(1.64g、7.62mmol)及びピロリジン(0.95mL、11.4mmol)から方法Aに従って、標題化合物を無色油状物として得、これを、さらには精製せずに次のステップに進行させた。

Step 1: (R) -tert-butyl (1-cyclopropyl-2-oxo-2- (pyrrolidin-1-yl) ethyl) carbamate
The title compound is obtained from (R) -2-((tert-butoxycarbonyl) amino) -2-cyclopropylacetic acid (1.64 g, 7.62 mmol) and pyrrolidine (0.95 mL, 11.4 mmol) as a colorless oil according to Method A. , This was taken to the next step without further purification.

Step 2: (R) -tert-butyl (1-cyclopropyl-2- (pyrrolidin-1-yl) ethyl) carbamate
The title compound was obtained from (R) -tert-butyl (1-cyclopropyl-2-oxo-2- (pyrrolidin-1-yl) ethyl) carbamate (1.02 g, 3.81 mmol) according to Method B, further. Used without purification.

Step 3: (R) -1-Cyclopropyl-2- (pyrrolidin-1-yl) ethaneamine
Follow Method C from (R) -tert-butyl (1-cyclopropyl-2- (pyrrolidin-1-yl) ethyl) carbamate (860 mg, 3.39 mmol). Dissolved in the residue obtained after aqueous post-treatment in DCM / MeOH (1: 1, 5 mL) and into SCX cartridge (DCM: MeOH: eluted with 7M NH ₃ (1: 1: 0.05) in MeOH) Free amine was isolated by passing. The title compound was obtained as an orange oil (190 mg, 36%).

Step 4: (R) -N- (1-cyclopropyl-2- (pyrrolidin-1-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3- Il) Benzamide
(R) -1-Cyclopropyl-2- (pyrrolidin-1-yl) ethaneamine (190 mg, 1.23 mmol) and 4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) ) Follow Method A from benzoic acid (212 mg, 0.82 mmol). LCMS (ES +) 395 (M + H) ⁺ , RT 2.69 minutes (analysis method 1). ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.42 (1H, d, J = 8.7 Hz), 8.15 (2H, d, J = 8.4 Hz), 8.05 (2H, d, J = 8.5 Hz), 3.71 --3.63 (1H, m), 2.80 (1H, dd, J = 9.1, 12.1 Hz), 2.52 --2.49 ( 3H, m), 2.48-2.40 (2H, m), 1.62 (4H, s), 1.02 --0.93 (1H, m), 0.50 --0.43 (1H, m), 0.36 --0.29 (2H, m), 0.24- 0.17 (1H, m).

[Example 7]
(R) -N- (1- (3,4-dihydroisoquinoline-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide

ステップ1:(R)-tert-ブチル(1-(3,4-ジヒドロイソキノリン-2(1H)-イル)-1-オキソプロパン-2-イル)カルバメート
(R)-2-((tert-ブトキシカルボニル)アミノ)プロパン酸(720mg、3.78mmol)及び1,2,3,4-テトラヒドロイソキノリン(0.52mL、4.016mmol)から方法Aに従う。カラムクロマトグラフィー(勾配溶出、i-hex中の0〜100%EtOAc)による精製によって、標題化合物を淡黄色ゴム状物として得た(1.01g、87%)。

Step 1: (R) -tert-butyl (1- (3,4-dihydroisoquinoline-2 (1H) -yl) -1-oxopropan-2-yl) carbamate
Follow Method A from (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (720 mg, 3.78 mmol) and 1,2,3,4-tetrahydroisoquinoline (0.52 mL, 4.016 mmol). Purification by column chromatography (gradient elution, 0-100% EtOAc in i-hex) gave the title compound as a pale yellow rubber (1.01 g, 87%).

Step 2: (R) -tert-butyl (1- (3,4-dihydroisoquinoline-2 (1H) -yl) propan-2-yl) carbamate
From (1- (3,4-dihydroisoquinoline-2 (1H) -yl) -1-oxopropan-2-yl) carbamate (1.01 g, 3.31 mmol) according to Method B, the title compound was made into a pale yellow rubbery substance. Obtained (0.86 mg, 89%).

Step 3: (R) -1- (3,4-dihydroisoquinoline-2 (1H) -yl) propan-2-amine dihydrochloride
From (R) -tert-butyl (1- (3,4-dihydroisoquinoline-2 (1H) -yl) propan-2-yl) carbamate (860 mg, 2.96 mmol) according to Method C, the title compound is in the form of a slightly orange glass. Obtained as a product (788 mg,> 99%). It was used in the next step without further purification.

Step 4: (R) -N- (1- (3,4-dihydroisoquinoline-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4 -Oxadiazole-3-yl) benzamide
From 4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (636 mg, 2.46 mmol) according to method A, (R) -1- (3,4-dihydro) Isoquinolin-2 (1H) -yl) propan-2-amine dihydrochloride (778 mg, 2.96 mmol) and DIPEA (2.2 mL, 12.3 mmol) were added and the mixture was stirred for 18 h. The mixture was washed with water, passed through a phase separation cartridge and concentrated to produce a crude product. The residue was purified by preparative-HPLC and then further purified by chiral SFC to give the title compound as a white solid. LCMS (ES +) 431 (M + H) ⁺ , RT 2.80 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.47 (1H, d, J = 8.2 Hz), 8.16 (2H, d, J = 8.5 Hz), 8.06 (2H, d, J = 8.7 Hz), 7.12 --7.04 (4H, m), 4.40 --4.32 (1H, m), 3.63 (2H, s), 2.82- 2.62 (6H, m), 1.22 (3H, d, J = 6.5 Hz).

[Example 8]
(R) -N- (1- (3-Phenylazetidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3- Il) Benzamide

ステップ1:(R)-tert-ブチル(1-オキソ-1-(3-フェニルアゼチジン-1-イル)プロパン-2-イル)カルバメート
(R)-2-((tert-ブトキシカルボニル)アミノ)プロパン酸(649mg、3.41mmol)及び3-フェニルアゼチジン(0.5g、3.75mmol)から方法Aに従う。カラムクロマトグラフィー(勾配溶出、0〜100%EtOAc/i-hex)による精製によって、標題化合物を無色ゴム状物として得た(0.87g、83%)。

Step 1: (R) -tert-butyl (1-oxo-1- (3-phenylazetidine-1-yl) propan-2-yl) carbamate
Follow Method A from (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (649 mg, 3.41 mmol) and 3-phenylazetidine (0.5 g, 3.75 mmol). Purification by column chromatography (gradient elution, 0-100% EtOAc / i-hex) gave the title compound as a colorless rubber (0.87 g, 83%).

Step 2: (R) -tert-butyl (1- (3-phenylazetidine-1-yl) propan-2-yl) carbamate
Follow Method B from (R) -tert-butyl (1-oxo-1- (3-phenylazetidine-1-yl) propan-2-yl) carbamate (0.87 g, 2.86 mmol). Purification by column chromatography (gradient elution, 0-100% EtOAc / i-hex) gave the title compound as a colorless oil (370 mg, 44%).

Step 3: (R) -1- (3-phenylazetidine-1-yl) propan-2-amine dihydrochloride
The title compound was obtained from (R) -tert-butyl (1- (3-phenylazetidine-1-yl) propan-2-yl) carbamate (370 mg, 1.27 mmol) as an off-white solid according to Method C ( 337 mg,> 99%). This material was taken to the next step without further purification.

Step 4: (R) -N- (1- (3-phenylazetidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole -3-Il) Benzamide
4- (5- (Trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (252 mg, 0.98 mmol) and (R) -1- (3-phenylazetidine-1-yl) ) Propane-2-amine dihydrochloride (348 mg, 1.07 mmol) according to Method A. After post-treatment, the crude material was recrystallized from diisopropyl ether three times to give the title compound as a white solid (71 mg, 16%). LCMS (ES +) 431 (M + H) ⁺ , RT 2.83 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.42 (1H, d, J = 8.0 Hz), 8.17 (2H, d, J = 8.4 Hz), 8.07 (2H, d, J = 8.5 Hz), 7.35 --7.28 (4H, m), 7.23 --7.18 (1H, m), 4.11 --4.00 (1H, m), 3.75 --3.57 (3H, m), 3.20 --3.07 (2H, m), 2.68 --2.57 (1H, m), 1.18 (3H, d, J = 6.8 Hz). One proton was hidden in the DMSO peak. ..

[Example 9 and Example 10]
D1: N-((R) -1-((abs) -3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2, 4-Oxadiazole-3-yl) benzamide; and D2: N-((R) -1-((abs) -3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) -4- (5- (Trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide

ステップ1:tert-ブチル((2R)-1-(3-(ジフルオロメトキシ)ピペリジン-1-イル)-1-オキソプロパン-2-イル)カルバメート
(R)-2-((tert-ブトキシカルボニル)アミノ)プロパン酸(284mg、1.50mmol)及び(±)-3-(ジフルオロメトキシ)ピペリジン(250mg、1.65mmol)から方法Aに従う。標題化合物を黄色ゴム状物として得(424mg、87%)、さらには精製せずに次のステップに使用した。

Step 1: tert-Butyl ((2R) -1-(3- (difluoromethoxy) piperidine-1-yl) -1-oxopropan-2-yl) carbamate
Follow Method A from (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (284 mg, 1.50 mmol) and (±) -3- (difluoromethoxy) piperidine (250 mg, 1.65 mmol). The title compound was obtained as a yellow rubbery product (424 mg, 87%) and was used in the next step without further purification.

Step 2: tert-Butyl ((2R) -1-(3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) carbamate
Follow Method B from tert-butyl ((2R) -1- (3- (difluoromethoxy) piperidine-1-yl) -1-oxopropan-2-yl) carbamate (420 mg, 1.30 mmol). The title compound was obtained as a pale yellow rubbery substance (234 mg, 58%).

Step 3: (2R) -1- (3- (difluoromethoxy) piperidine-1-yl) propan-2-amine dihydrochloride
Follow Method C from tert-butyl ((2R) -1- (3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) carbamate (234 mg, 0.76 mmol). The title compound was obtained as a pale yellow foam (210 mg, 98%).

Step 4: D1: N-((R) -1-((abs) -3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1 , 2,4-Oxadiazole-3-yl) benzamide; and D2: N-((R) -1-((abs) -3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide.
4- (5- (Trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (178 mg, 0.69 mmol) and (2R) -1- (3- (difluoromethoxy) piperidine-1 -Il) Propane-2-amine Follow Method A from dihydrochloride (210 mg, 0.76 mmol). The crude material was purified by preparative HPLC and chiral preparative SFC (LUX Cellulose-4, 5/95 IPA / CO ₂ , 5.0 ml / min, 120 bar, 40 ° C.) to give the title compound as a white solid. D1: N-((R) -1-((abs) -3- (difluoromethoxy) piperidin-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2, 4-Oxaziazole-3-yl) benzamide (50 mg, 16%): LCMS (ES +) 449 (M + H) ⁺ , RT 2.74 minutes (analysis method 1); SFC RT 4.48 minutes; ¹ H NMR δ (ppm) ) (400 MHz, DMSO-d ₆ ) 8.40 (1H, d, J = 8.3 Hz), 8.17 (2H, d, J = 8.5 Hz), 8.05 (2H, d, J = 8.5 Hz), 6.72 (1H, 1H, t, J = 76.3 Hz), 4.27 --4.16 (1H, m), 4.10 --4.01 (1H, m), 2.91 (1H, dd, J = 3.0, 10.4 Hz), 2.68 --2.60 (1H, m), 2.35 (1H, dd, J = 7.0, 12.4 Hz), 2.19 --2.05 (2H, m), 1.91 --1.82 (1H, m), 1.71 --1.63 (1H, m), 1.47 --1.27 (2H, m), 1.16 (3H, d, J = 6.5 Hz). One proton was concealed at the DMSO peak. D2: N-((R) -1-((abs) -3- (difluoromethoxy) piperidin-1-yl) ) Propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl) benzamide (53g, 17%): LCMS (ES +) 449 (M + H) ) ⁺ , RT 2.72 minutes (analysis method 1); SFC RT 7.49 minutes; ¹ H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.40 (1H, d, J = 8.2 Hz), 8.17 (2H, d) , J = 8.5 Hz), 8.05 (2H, d, J = 8.5 Hz), 6.73 (1H, t, J = 76.4 Hz), 4.27 --4.16 (1H, m), 4.11 --4.02 (1H, m), 2.92 (1H, dd, J = 3.3, 10.6 Hz), 2.72 --2.67 (1H, m), 2.35 (1H, dd, J = 6.7, 12.5 Hz), 2.15 --2.02 (2H) , m), 1.92 --1.83 (1H, m), 1.70 --1.62 (1H, m), 1.46 --1.25 (2H, m), 1.16 (3H, d, J = 6.7 Hz). One proton at DMSO peak It was hidden.

[Example 11]
(R) -N- (1- (5-azaspiro [2.5] octane-5-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide

ステップ1:(R)-tert-ブチル(1-オキソ-1-(5-アザスピロ[2.5]オクタン-5-イル)プロパン-2-イル)カルバメート
(R)-2-((tert-ブトキシカルボニル)アミノ)プロパン酸(648mg、3.43mmol)のDMF(10mL)撹拌溶液に、HBTU(1.43g、3.73mmol)、5-アザスピロ[2.5]オクタン塩酸塩(500mg、3.43mmol)及びDIPEA(3.16mL、17.1mmol)を加えた。混合物を、室温で終夜撹拌した。混合物を、水で洗浄し、相分離カートリッジに通し、濃縮して、標題化合物を得(1.01g)、これを、さらには精製せずに次のステップに使用した。

Step 1: (R) -tert-butyl (1-oxo-1- (5-azaspiro [2.5] octane-5-yl) propan-2-yl) carbamate
HBTU (1.43 g, 3.73 mmol), 5-azaspiro [2.5] octane hydrochloride in a stirred solution of (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (648 mg, 3.43 mmol) in DMF (10 mL). (500 mg, 3.43 mmol) and DIPEA (3.16 mL, 17.1 mmol) were added. The mixture was stirred at room temperature overnight. The mixture was washed with water, passed through a phase separation cartridge and concentrated to give the title compound (1.01 g), which was used in the next step without further purification.

Step 2: (R) -tert-butyl (1- (5-azaspiro [2.5] octane-5-yl) propan-2-yl) carbamate
The title compound by following Method B from (R) -tert-butyl (1-oxo-1- (5-azaspiro [2.5] octane-5-yl) propan-2-yl) carbamate (1.01 g, 3.58 mmol). Was used in the next step without further purification.

Step 3: (R) -1- (5-azaspiro [2.5] octane-5-yl) propan-2-amine dihydrochloride
The title compound was obtained from (R) -tert-butyl (1- (5-azaspiro [2.5] octane-5-yl) propan-2-yl) carbamate (866 mg, 2.29 mmol) by following Method C. , And used in the next step without further purification.

Step 4: (R) -N- (1- (5-azaspiro [2.5] octane-5-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxa Diazol-3-yl) benzamide
4- (5- (Trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (590 mg, 2.29 mmol) and (R) -1- (5-azaspiro [2.5] octane-5 -Il) Propane-2-amine Dihydrochloride (770 mg, 2.29 mmol) using the same method as in step 1. The title compound was obtained as a white solid. LCMS (ES +) 409 (M + H) ⁺ , RT 3.58 minutes (analysis method 2); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.38 (1H, d, J = 8.2 Hz), 8.19 (2H, d, J = 8.5 Hz), 8.07 (2H, d, J = 8.5 Hz), 4.24 --4.16 (1H, m), 2.49 --2.41 (2H, m), 2.29 (1H, dd, J = 7.2) , 12.2 Hz), 2.18 (2H, dd, J = 11.8, 17.5 Hz), 1.63 --1.57 (2H, m), 1.32 --1.22 (3H, m), 1.17 (3H, d, J = 6.5 Hz), 0.31 --0.22 (4H, m).

[Example 12]
(R) -N- (1- (6-azaspiro [2.5] octane-6-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide

ステップ1:(R)-tert-ブチル(1-オキソ-1-(6-アザスピロ[2.5]オクタン-6-イル)プロパン-2-イル)カルバメート
フラスコに、(R)-2-((tert-ブトキシカルボニル)アミノ)プロパン酸(250mg、1.32mmol)、6-アザスピロ[2.5]オクタン(150mg、1.32mmol)、HATU(602mg、1.60mmol)及び無水DMF(5mL)を充てんした。反応混合物を、淡黄色の溶液が形成されるまで撹拌し、次いで、DIPEA(350μL、2.0mmol)を加え、混合物を終夜撹拌した。反応混合物を、EtOAc(25mL)で希釈し、1M HCl(15mL)、飽和NaHCO₃(15mL)、次いで、食塩水(15mL)で洗浄した。有機物を、(MgSO₄)で乾燥し、濾過し、濃縮した。カラムクロマトグラフィー(勾配溶出、i-hex中の0〜66%EtOAc)による精製によって、標題化合物を無色油状物として得(339mg、91%)、これを放置するとき凝固する。

Step 1: In a (R) -tert-butyl (1-oxo-1- (6-azaspiro [2.5] octane-6-yl) propan-2-yl) carbamate flask, (R) -2-((tert-) It was filled with butoxycarbonyl) amino) propanoic acid (250 mg, 1.32 mmol), 6-azaspiro [2.5] octane (150 mg, 1.32 mmol), HATU (602 mg, 1.60 mmol) and anhydrous DMF (5 mL). The reaction mixture was stirred until a pale yellow solution was formed, then DIPEA (350 μL, 2.0 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with EtOAc (25 mL) and washed with 1M HCl (15 mL), saturated LVDS ₃ (15 mL) and then saline (15 mL). The organics were dried over (DDL ₄ ), filtered and concentrated. Purification by column chromatography (gradient elution, 0-66% EtOAc in i-hex) gives the title compound as a colorless oil (339 mg, 91%), which coagulates when left to stand.

Step 2: (R) -tert-butyl (1- (6-azaspiro [2.5] octane-6-yl) propan-2-yl) carbamate
Method B (instead of Et ₂ O) from (R) -tert-butyl (1-oxo-1- (6-azaspiro [2.5] octane-6-yl) propan-2-yl) carbamate (320 mg, 1.13 mmol) The title compound was obtained as a pale yellow oil (260 mg, 86%) according to (using THF).

Step 3: (R) -1- (6-azaspiro [2.5] octane-6-yl) propan-2-amine
TFA (1.5 mL) in anhydrous DCM (10 mL) solution of (R) -tert-butyl (1- (6-azaspiro [2.5] octane-6-yl) propan-2-yl) carbamate (220 mg, 0.82 mmol) Was added. The reaction mixture was stirred at room temperature for 48 h. The mixture was concentrated under reduced pressure and passed through an SCX cartridge (MeOH: eluted with 7M NH ₃ (4: 1) in MeOH). The basic fraction was concentrated to give the title compound as a brown oil (120 mg, 85%).

Step 4: (R) -N- (1- (6-azaspiro [2.5] octane-6-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxa Diazol-3-yl) benzamide
4- (5- (Trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (124 mg, 0.48 mmol) and (R) -1- (6-azaspiro [2.5] octane-6 -Il) Propane-2-amine (80 mg, 0.48 mmol) from step 1 follow the same procedure. Purification by preparative HPLC gave the title compound as a colorless solid. LCMS (ES +) 409 (M + H) ⁺ , RT 2.77 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.16 (1 H, d, J = 8.1 Hz), 7.96-7.90 (2 H, m), 7.82 (2 H, d, J = 8.3 Hz), 4.00 (1 H, t, J = 7.2 Hz), 3.10 (4 H, br s), 2.2.30-2.20 (5 H, s), 2.14-2.08 (1 H, m), 1.08 (4 H, s), 0.93 (3 H, t, J = 6.6 Hz).

[Example 13]
(R) -N- (1- (azepan-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide

ステップ1:(R)-tert-ブチル(1-(アゼパン-1-イル)プロパン-2-イル)カルバメート
中間体1(1.0g、3.95mmol)及びアゼパン(890μL、7.91mmol)から方法Dに従って、標題化合物を黄色油状物として得た(489mg、48%)。

Step 1: From (R) -tert-butyl (1- (azepan-1-yl) propan-2-yl) carbamate intermediate 1 (1.0 g, 3.95 mmol) and azepan (890 μL, 7.91 mmol) according to method D. The title compound was obtained as a yellow oil (489 mg, 48%).

Step 2: (R) -1- (azepan-1-yl) propan-2-amine
TFA (0.8 mL) was obtained in anhydrous DCM (40 mL) solution of (R) -tert-butyl (1- (azepan-1-yl) propan-2-yl) carbamate (489 mg, 1.91 mmol). The reaction mixture was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and passed through an SCX cartridge (MeOH: eluted with 7M NH ₃ (4: 1) in MeOH). The basic fraction was concentrated to give the title compound as a yellow oil (310 mg,> 99%).

Step 3: (R) -N- (1- (azepan-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) ) Benzamide
4- (5- (Trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (427 mg, 1.65 mmol) and (R) -1- (azepan-1-yl) propane-2 -Follow Method A with amine (310 mg, 1.91 mmol). Preparative-purification by HPLC and SFC gave the title compound as a white solid (45 mg). LCMS (ES +) 397 (M + H) ⁺ , RT 2.70 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.35 (1H, d, J = 8.2 Hz), 8.17 (2H, d, J = 8.7 Hz), 8.05 (2H, d, J = 8.5 Hz), 4.17 --4.09 (1H, m), 2.68 --2.59 (5H, m), 2.45 (1H, dd, J = 7.0) , 12.4 Hz), 1.58 --1.51 (8H, m), 1.16 (3H, d, J = 6.7 Hz).

[Example 14]
(R) -N- (1- (1-azaspiro [3.3] heptane-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide

ステップ1:(R)-tert-ブチル(1-(1-アザスピロ[3.3]ヘプタン-1-イル)プロパン-2-イル)カルバメート
中間体1(326mg、1.29mmol)及び1-アザスピロ[3.3]ヘプタン(250mg、2.53mmol)から方法Dに従って、標題化合物(250mg)を得、これを、さらには精製せずに次のステップに使用した。

Step 1: (R) -tert-butyl (1- (1-azaspiro [3.3] heptane-1-yl) propan-2-yl) carbamate intermediate 1 (326 mg, 1.29 mmol) and 1-azaspiro [3.3] heptane The title compound (250 mg) was obtained from (250 mg, 2.53 mmol) according to Method D, which was used in the next step without further purification.

Step 2: 1-((R) -2-aminopropyl) -1-azaspiro [3.3] heptane-1-ium 2,2,2-trifluoroacetate
TFA (1 mL) in anhydrous DCM (2 mL) solution of (R) -tert-butyl (1- (1-azaspir [3.3] heptane-1-yl) propan-2-yl) carbamate (0.25 mg, 1.00 mmol) Was added. The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to give the title compound (268 mg), which was used in the next step without further purification.

Step 3: (R) -N- (1- (1-azaspiro [3.3] heptane-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxa In a diazole-3-yl) benzamide flask, (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (260 mg, 1.00 mmol), 1-((R) -2-aminopropyl) -1- Azaspiro [3.3] heptane-1-ium 2,2,2-trifluoroacetic acid (268 mg, 1.00 mmol), HATU (690 mg, 1.5 mmol), DMAP (30 mg) and anhydrous DMF (5 mL) were filled. The reaction mixture was stirred until a pale yellow solution was formed, then DIPEA (1.5 mL, 72.0 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with DCM, washed with water, passed through a phase separator, filtered and concentrated. Preparative-purification by HPLC and SFC gave the title compound as a white solid (12 mg). LCMS (ES +) 395 (M + H) ⁺ , RT 2.65 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.42 (1H, d, J = 8.1 Hz), 8.21 (2H, d, J = 8.6 Hz), 8.11 (2H, d, J = 8.6 Hz), 4.11 --4.02 (1H, m), 3.15 --3.08 (2H, m), 2.63 (1H, dd, J = 6.4) , 11.7 Hz), 2.49 (1H, dd, J = 7.1, 11.9 Hz), 2.27 --2.09 (4H, m), 1.90 (2H, m), 1.64 --1.56 (2H, m), 1.21 (3H, d, J = 6.8 Hz).

[Example 15]
(R) -N- (1- (5-azaspiro [2.4] heptane-5-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide

ステップ1:(R)-tert-ブチル(1-(5-アザスピロ[2.4]ヘプタン-5-イル)プロパン-2-イル)カルバメート
中間体1(237mg、0.90mmol)及び5-アザスピロ[2.4]ヘプタン-5-イウムクロリド(250mg、1.80mmol)から方法Dに従って、標題化合物(100mg)を得、これを、さらには精製せずに次のステップに使用した。

Step 1: (R) -tert-butyl (1- (5-azaspiro [2.4] heptane-5-yl) propan-2-yl) carbamate intermediate 1 (237 mg, 0.90 mmol) and 5-azaspiro [2.4] heptane The title compound (100 mg) was obtained from -5-ium chloride (250 mg, 1.80 mmol) according to Method D, which was used in the next step without further purification.

Step 2: 5-((R) -2-aminopropyl) -5-azaspiro [2.4] heptane-5-ium 2,2,2-trifluoroacetate
TFA (1 mL) in a solution of (R) -tert-butyl (1- (1-azaspir [3.3] heptane-1-yl) propan-2-yl) carbamate (0.25 mg, 1.00 mmol) in anhydrous DCM (2 mL). ) Was added. The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure to give the title compound (268 mg), which was used in the next step without further purification.

Step 3: (R) -N- (1- (1-azaspiro [3.3] heptane-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxa In a diazole-3-yl) benzamide flask, (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (260 mg, 1.00 mmol), (R) -1- (1-azaspiro [3.3] heptane- It was filled with 1-yl) propan-2-amine (268 mg, 1.00 mmol), HATU (690 mg, 1.5 mmol), DMAP (30 mg) and anhydrous DMF (5 mL). The reaction mixture was stirred until a pale yellow solution was formed, then DIPEA (1.5 mL, 72.0 mmol) was added and the mixture was stirred overnight. The reaction mixture was diluted with DCM, washed with water, passed through a phase separator, filtered and concentrated. Preparative-purification by HPLC and SFC gave the title compound as a white solid (12 mg). LCMS (ES +) 395 (M + H) ⁺ , RT 2.65 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.48 (1H, d, J = 8.1 Hz), 8.22 (2H, d, J = 8.6 Hz), 8.12 (2H, d, J = 8.3 Hz), 4.24 --4.16 (1H, m), 2.73 (2H, dd, J = 6.9, 6.9 Hz), 2.62 (2H, 2H, dd, J = 7.3, 11.6 Hz), 2.52 --2.48 (2H, m), 1.79 --1.74 (2H, m), 1.23 (3H, d, J = 6.6 Hz), 0.54 (4H, dd, J = 7.6, 18.9 Hz).

[Example 16]
N-((2R) -1- (3-azabicyclo [3.2.1] octane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide

ステップ1:tert-ブチル((R)-1-((1R,5S)-3-アザビシクロ[3.2.1]オクタン-3-イル)プロパン-2-イル)カルバメート
中間体1(736mg、2.90mmol)及び(1R,5S)-3-アザビシクロ[3.2.1]オクタン(730mg、4.94mmol)から方法Dに従って、標題化合物(186mg、21%)を得、これを、さらには精製せずに次のステップに使用した。

Step 1: tert-Butyl ((R) -1-((1R, 5S) -3-azabicyclo [3.2.1] octane-3-yl) propan-2-yl) carbamate intermediate 1 (736 mg, 2.90 mmol) And (1R, 5S) -3-azabicyclo [3.2.1] octane (730 mg, 4.94 mmol) according to Method D to give the title compound (186 mg, 21%), which is further unpurified to the next step. Used for.

Step 2: (R) -1-((1R, 5S) -3-azabicyclo [3.2.1] octane-3-yl) propan-2-amine
Anhydrous DCM (2.5 mL) of tert-butyl ((R) -1-((1R, 5S) -3-azabicyclo [3.2.1] octane-3-yl) propan-2-yl) carbamate (186 mg, 0.62 mmol) ) TFA (0.5 mL) was added to the solution. The reaction mixture was stirred at room temperature for 3 h. The mixture was concentrated under reduced pressure and passed through an SCX cartridge (MeOH: eluted with 7M NH ₃ (4: 1) in MeOH). The basic fraction was concentrated to give the title compound (80 mg), which was used in the next step without further purification.

Step 3: N-((R) -1-((1R, 5S) -3-azabicyclo [3.2.1] octane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide
4- (5- (Trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (122 mg, 0.47 mmol) and (R) -1- (3-azabicyclo [3.2.1] octane Follow Method A from -3-yl) propan-2-amine (80 mg, 0.47 mmol). Preparative-purification by HPLC and SFC gave the title compound as a white solid (33 mg). LCMS (ES +) 409 (M + H) ⁺ , RT 2.81 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.31 (1H, d, J = 8.3 Hz), 8.17 (2H, d, J = 8.7 Hz), 8.05 (2H, d, J = 8.5 Hz), 4.24 --4.16 (1H, m), 2.73 --2.61 (2H, m), 2.41 (1H, dd, J = 8.3) , 12.2 Hz), 2.26 (1H, dd, J = 6.7, 12.2 Hz), 2.11 --1.99 (4H, m), 1.55 --1.36 (5H, m), 1.29 (1H, d, J = 10.4 Hz), 1.15 (3H, d, J = 6.5 Hz).

[Example 17]
2-((R) -2-(4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl) octahydrocyclopenta [c] pyrrole-2- Iumformate

ステップ1:tert-ブチル((2R)-1-(ヘキサヒドロシクロペンタ[c]ピロール-2(1H)-イル)-1-オキソプロパン-2-イル)カルバメート
(R)-2-((tert-ブトキシカルボニル)アミノ)プロパン酸(0.77g、4.09mmol)及びオクタヒドロシクロペンタ[c]ピロール(0.50g、4.5mmol)から方法Aに従って、標題化合物を黄色ゴム状物として得た(1.08g、93%)。化合物は、不純であったが、さらには精製せずに次のステップに使用した。

Step 1: tert-Butyl ((2R) -1- (hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) -1-oxopropan-2-yl) carbamate
Yellow rubber from (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (0.77 g, 4.09 mmol) and octahydrocyclopenta [c] pyrrole (0.50 g, 4.5 mmol) according to Method A. Obtained as a compound (1.08 g, 93%). The compound was impure but was used in the next step without further purification.

Step 2: tert-Butyl ((2R) -1- (hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) -1-oxopropan-2-yl) carbamate
From tert-butyl ((2R) -1- (hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) -1-oxopropan-2-yl) carbamate (1.08 g, 3.82 mmol) according to method B. The title compound was obtained as a pale yellow rubbery substance (0.61 g, 59%). The compound was impure but was used in the next step without further purification.

Step 3: (2R) -1- (hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) propan-2-amine hydrochloride
From tert-butyl ((2R) -1- (hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) -1-oxopropan-2-yl) carbamate (0.61 g, 2.27 mmol) according to method C. The title compound was obtained as a pale yellow foam (274 mg,> 100%). It was used in the next step without further purification.

Step 4: 2-((R) -2-(4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl) octahydrocyclopenta [c] pyrrole -2-Iumformate
Follow Method A from 4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (0.48 g, 1.89 mmol). Purification by column chromatography using gradient elution of 0-20% methanol in DCM gave a slightly orange solid (700 mg). This was further purified by preparative HPLC to give the title compound as a slightly orange glass (142 mg). LCMS (ES +) 409 (M + H) ⁺ , RT 2.74 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.40 (1H, d, J = 8.2 Hz), 8.19 --8.15 (3H, m), 8.05 (2H, d, J = 8.5 Hz), 4.23 --4.11 (1H, m), 2.60 (2H, q, J = 7.5 Hz), 2.49 --2.43 (3H, m), 2.43 --2.38 (1H, m), 2.25 (2H, ddd, J = 3.9, 8.4, 12.0 Hz), 1.59 --1.52 (3H, m), 1.41 --1.29 (3H, m), 1.17 (3H, d, J) = 6.7 Hz).

[Example 18]
(R) -N- (1- (3,4-dihydro-2,7-naphthylidine-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2 , 4-Oxadiazole-3-yl) benzamide

ステップ1:(R)-tert-ブチル(1-(3,4-ジヒドロ-2,6-ナフチリジン-2(1H)-イル)-1-オキソプロパン-2-イル)カルバメート
(R)-2-((tert-ブトキシカルボニル)アミノ)プロパン酸(1.28g、6.78mmol)及び1,2,3,4-テトラヒドロ-2,6-ナフチリジン(1.0g、7.45mmol)から方法Aに従う。標題化合物を淡黄色ゴム状物として得た(2.43g、>100%)。これによって、未精製物を次のステップに使用した。

Step 1: (R) -tert-butyl (1- (3,4-dihydro-2,6-naphthylidine-2 (1H) -yl) -1-oxopropan-2-yl) carbamate
Method A from (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (1.28 g, 6.78 mmol) and 1,2,3,4-tetrahydro-2,6-naphthylidine (1.0 g, 7.45 mmol) Follow. The title compound was obtained as a pale yellow rubbery substance (2.43 g,> 100%). This allowed the unrefined product to be used in the next step.

Step 2: (R) -tert-butyl (1- (3,4-dihydro-2,6-naphthalene-2 (1H) -yl) propan-2-yl) carbamate
Method from (R) -tert-butyl (1- (3,4-dihydro-2,6-naphthylidine-2 (1H) -yl) -1-oxopropan-2-yl) carbamate (2.43 g, 7.96 mmol) Follow B. The mixture was purified by passing through an SCX cartridge (MeOH: eluted with 7M NH ₃ (9: 1) in MeOH). This gave the title compound as a pale yellow rubbery substance (810 mg, 34%). The product was used in the next step without further purification.

Step 3: (R) -1- (3,4-dihydro-2,6-naphthylidine-2 (1H) -yl) propan-2-amine trihydrochloride
The title compound from (R) -tert-butyl (1- (3,4-dihydro-2,6-naphthylidine-2 (1H) -yl) propan-2-yl) carbamate (810 mg, 2.78 mmol) according to Method C. Was obtained as a slightly orange glassy substance (0.98 mg,> 100%). It was used in the next step without further purification.

Step 4: (R) -N-(1- (3,4-dihydro-2,7-naphthylidine-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl)- 1,2,4-oxadiazole-3-yl) benzamide
From 4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (650 mg, 2.5 mmol) according to method A, (R) -1- (3,4-dihydro) -2,6-naphthylidine-2 (1H) -yl) propan-2-amine trihydrochloride (980 mg, 2.78 mmol) and DIPEA (2.2 mL, 12.5 mmol) were added and the mixture was stirred for 18 h. The mixture was washed with water, passed through a phase separation cartridge and concentrated to produce a crude product. Preparative-purification by HPLC gave the title compound as an off-white solid (162 mg). LCMS (ES +) 432 (M + H) ⁺ , RT 2.41 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.48 (1H, d, J = 8.2 Hz), 8.29 (1H, s), 8.26 (1H, d, J = 5.0 Hz), 8.16 (3H, d, J = 7.8 Hz), 8.06 (2H, d, J = 8.5 Hz), 7.11 (1H, d, J = 5.1 Hz), 4.42 --4.30 (1H, m), 3.66 (2H, s), 2.81 --2.64 (6H, m), 1.22 (3H, d, J = 6.5 Hz).

[Example 19]
N-((2R) -1- (3-azabicyclo [3.2.0] heptane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide

ステップ1:3-(4-メトキシベンジル)-3-アザビシクロ[3.2.0]ヘプタン-2,4-ジオン
4-メトキシベンジルアミン(1.04mL、7.93mmol)を、0℃で、3-オキサビシクロ[3.2.0]ヘプタン-2,4-ジオン(1.0g、7.93mmol)のTHF(3mL)溶液に滴加した。半固形の混合物を、90℃まで加温して、THFを除去し、混合物としてゆっくりと融解した固体を、2h180℃まで加温した。溶液を60℃まで冷却し、氷冷したDIPE中に注いで、標題化合物を白色固体として生成し(1.77g、91%)、これを濾過により収集した。

Step 1: 3- (4-Methoxybenzyl) -3-azabicyclo [3.2.0] heptane-2,4-dione
4-Methoxybenzylamine (1.04 mL, 7.93 mmol) is added dropwise to a solution of 3-oxabicyclo [3.2.0] heptane-2,4-dione (1.0 g, 7.93 mmol) in THF (3 mL) at 0 ° C. did. The semi-solid mixture was heated to 90 ° C. to remove THF and the slowly melted solid as a mixture was heated to 2h 180 ° C. The solution was cooled to 60 ° C. and poured into ice-cooled DIPE to produce the title compound as a white solid (1.77 g, 91%), which was collected by filtration.

Step 2: 3- (4-Methoxybenzyl) -3-azabicyclo [3.2.0] heptane
Follow Method B from 3- (4-methoxybenzyl) -3-azabicyclo [3.2.0] heptane-2,4-dione (1.0 g, 4.1 mmol). The reaction was refluxed for 2 hours and then worked up. As a result, the title compound was obtained as a pale yellow rubbery substance (1.0 g). The product was used in the next step without further purification.

Step 3: 3-Azabicyclo [3.2.0] heptane hydrochloride
3- (4-Methoxybenzyl) -3-azabicyclo [3.2.0] heptane (870 mg, 4.0 mmol) was dissolved in MeOH (100 mL) and 10% Pd / C (870 mg) was added. The mixture was shaken in a hydrogen gas atmosphere (2 bar) for 18 hours at room temperature. The reaction mixture is then filtered through Celite, acidified with 4N HCl in dioxane (5 mL) and concentrated to produce the title compound as an off-white vitreous (590 mg), which is further purified. Used for the next step without.

Step 4: tert-Butyl ((2R) -1- (3-azabicyclo [3.2.0] heptane-3-yl) -1-oxopropan-2-yl) carbamate
Follow Method A from (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (630 mg, 3.33 mmol) and 3-azabicyclo [3.2.0] heptane hydrochloride (590 mg, 4.0 mmol). The title compound was obtained as a pale yellow rubbery substance (490 mg, 55%). This allowed the unrefined product to be used in the next step.

Step 5: tert-Butyl ((2R) -1- (3-azabicyclo [3.2.0] heptane-3-yl) propan-2-yl) carbamate
Follow Method B from tert-butyl ((2R) -1- (3-azabicyclo [3.2.0] heptane-3-yl) -1-oxopropan-2-yl) carbamate (0.49 g, 1.80 mmol). The mixture was purified by passing it through an SCX cartridge (MeOH: eluted with 7M NH ₃ (9: 1) in MeOH). This gave the title compound as a pale yellow rubber (229 mg, 49%).

Step 6: (2R) -1- (3-azabicyclo [3.2.0] heptane-3-yl) propan-2-amine hydrochloride
From tert-butyl ((2R) -1- (3-azabicyclo [3.2.0] heptane-3-yl) propan-2-yl) carbamate (490 mg, 0.90 mmol) according to Method C, the title compound as a pale yellow solid. Obtained (254 mg,> 100%). It was used in the next step without further purification.

Step 7: N-((2R) -1- (3-azabicyclo [3.2.0] heptane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4 -Oxadiazole-3-yl) benzamide
From 4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (211 mg, 0.82 mmol) according to method A, (2R) -1- (3-azabicyclo [3.2) .0] Heptan-3-yl) propan-2-amine hydrochloride (254 mg, 0.90 mmol) and DIPEA (0.73 mL, 4.09 mmol) were added and the mixture was stirred for 18 h. The mixture was washed with water, passed through a phase separation cartridge and concentrated to produce a crude product. The residue was purified by preparative-HPLC and then further purified by chiral SFC to give the title compound as a white solid (65 mg). LCMS (ES +) 395 (M + H) ⁺ , RT 2.71 min (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.44 (1H, d, J = 8.3 Hz), 8.17 (2H, d, J = 8.5 Hz), 8.06 (2H, d, J = 8.7 Hz), 4.31 --4.22 (1H, m), 2.83 (2H, dd, J = 9.0, 29.3 Hz), 2.75 --2.66 ( 2H, m), 2.61 (1H, dd, J = 7.7, 11.6 Hz), 2.53-2.50 (1H, m, hidden in DMSO), 2.06 --1.98 (4H, m), 1.61 --1.56 (2H, m) m), 1.25 (3H, d, J = 6.5 Hz).

[Examples 20 and 21]
D1: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl) propan-2-yl) -4- (5- (tri) Fluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide; and D2: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] ] Heptan-6-yl) Propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide

ステップ1:6-アザビシクロ[3.2.0]ヘプタン塩酸塩
アザビシクロ[3.2.0]ヘプタン-7-オン(500mg、4.49mmol)のジエチルエーテル(9mL)溶液を、LiAlH₄(5.6mL、11.2mmol)のジエチルエーテル(36mL)還流溶液に0.5hにわたって滴加した。反応混合物を24h還流し、0℃まで冷却し、次いで、水(3mL)、2N NaOH溶液(4mL)及び水(8mL)を、順次加えた。反応物を、室温まで加温し、30分間撹拌し、次いで、MgSO₄を加え、反応物をセライトで濾過し、EtOAcで十分に洗浄した。ろ液を、ジオキサン(5mL)中で4N HClで酸性にし、濃縮して、標題化合物を不透明なゴム状物として得た(270mg、45%)。粗物質を、さらには精製せずに次のステップに利用した。

Step 1: 6-Azabicyclo [3.2.0] heptane hydrochloride Azabicyclo [3.2.0] heptane-7-one (500 mg, 4.49 mmol) in diethyl ether (9 mL) in LiAlH ₄ (5.6 mL, 11.2 mmol). It was added dropwise to a reflux solution of diethyl ether (36 mL) over 0.5 h. The reaction mixture was refluxed for 24 h, cooled to 0 ° C., then water (3 mL), 2N NaOH solution (4 mL) and water (8 mL) were added sequentially. The reaction was warmed to room temperature, stirred for 30 minutes, then DDL ₄ was added, the reaction was filtered through Celite and washed thoroughly with EtOAc. The filtrate was acidified with 4N HCl in dioxane (5 mL) and concentrated to give the title compound as an opaque rubbery substance (270 mg, 45%). The crude material was used in the next step without further purification.

Step 2: tert-Butyl ((2R) -1- (6-azabicyclo [3.2.0] heptane-6-yl) -1-oxopropan-2-yl) carbamate
Follow Method A from (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (1.28 mg, 6.78 mmol) and 6-azabicyclo [3.2.0] heptane hydrochloride (270 mg, 2.78 mmol). The title compound was obtained as a pale yellow rubbery substance (0.61 mg, 89%). This allowed the unrefined product to be used in the next step.

Step 3: tert-Butyl ((2R) -1- (bicyclo [3.2.0] heptane-6-yl) propan-2-yl) carbamate (two diastereomers)
Follow Method B from tert-butyl ((2R) -1- (6-azabicyclo [3.2.0] heptane-6-yl) -1-oxopropan-2-yl) carbamate (0.61 g, 2.27 mmol). The mixture was purified by passing through an SCX cartridge (MeOH: eluted with 7M NH ₃ (9: 1) in MeOH). This gave a mixture of the two diastereomers of the title compound as a pale yellow rubbery (250 mg, 43%).

Step 4: (2R) -1- (6-azabicyclo [3.2.0] heptane-6-yl) propan-2-amine dihydrochloride (two diastereomers)
From tert-butyl ((2R) -1- (bicyclo [3.2.0] heptane-6-yl) propan-2-yl) carbamate (250 mg, 0.97 mmol) according to method C of the two diastereomers of the title compound The mixture was obtained as a pale yellow solid (257 mg). It was used in the next step without further purification.

Step 5: D1: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl) propan-2-yl) -4- (5) -(Trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide; and D2: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [ 3.2.0] Heptane-6-yl) Propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide
From 4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (228 mg, 0.88 mmol) according to method A, (2R) -1- (6-azabicyclo [3.2) .0] Heptan-6-yl) propan-2-amine dihydrochloride (257 mg, 0.98 mmol) and DIPEA (0.79 mL, 4.43 mmol) were added and the mixture was stirred for 18 h. The mixture was washed with water, passed through a phase separation cartridge and concentrated to produce a crude product. This residue was purified by preparative-HPLC and then further purified by chiral preparative SFC (LUX CELLUOSE-4 10/90 MeOH (0.1% DEA) / CO ₂ , 5.0 ml / min, 120 bar, 40 ° C). The title compound was obtained as a white solid. D1: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl) propan-2-yl) -4- (5- (tri) Fluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide (8 mg). LCMS (ES +) 395 (M + H) ⁺ , RT 3.67 minutes (analysis method 2); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.34 (1H, br s), 8.17 (2H, d) , J = 8.3 Hz), 8.05 (2H, d, J = 8.4 Hz), 3.93 (1H, br s), 3.73 (1H, br s), 3.14 (1H, br s), 2.98 (1H, br s) , 2.76 (1H, br s), 2.63 (1H, br s), 2.47 (1H, br s), 2.02- 1.90 (1H, m), 1.78 ―― 1.60 (3H, m), 1.46 ―― 1.35 (1H, m) ), 1.13 (4H, d, J = 6.5 Hz). D2: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl)) Propane-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazol-3-yl) benzamide (4 mg). LCMS (ES +) 395 (M + H) ⁺ , RT 3.67 minutes (analysis method 2); ^{1 1} H NMR (400 MHz, DMSO) 8.31 (1H, d, J = 8.2 Hz), 8.17 (2H, d, J = 8.5 Hz), 8.04 (2H, d, J = 8.5 Hz) Hz), 3.94 --3.86 (1H, m), 3.65 (1H, dd, J = 4.7, 6.0 Hz), 3.18 (1H, dd, J = 7.9, 7.9 Hz), 2.93 (1H, dd, J = 3.3, 7.5 Hz), 2.78 --2.72 (1H, m), 2.61 (1H, dd, J = 8.1, 11.3 Hz), 2.46 (1H, dd, J = 5.9, 11.9 Hz), 1.99 --1.90 (1H, m), 1.73 --1.56 (3H, m), 1.45 --1.34 (1H, m), 1.17 --1.13 (1H, m), 1.10 (3H, d, J = 6.7 Hz).

[Example 22]
N-((2R) -1- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1, 2,4-Oxadiazole-3-yl) benzamide

ステップ1:3-(2,4-ジメトキシベンジル)-6,6-ジメチル-3-アザビシクロ[3.1.0]ヘキサン-2,4-ジオン
2,4-ジメトキシベンジルアミン(1.45g、8.67mmol)を、6,6-ジメチル-3-オキサビシクロ[3.1.0]ヘキサン-2,4-ジオン(1.21g、8.67mmol)のTHF(5mL)溶液に0℃で滴加した。半固形の混合物を90℃まで加温して、THFを除去し、混合物としてゆっくりと融解した固体を、2h180℃まで加温した。溶液を、-60℃まで冷却し、氷冷したDIPEに注ぎ、ゴム状物を形成させた。これを、分離し、蒸発させて、標題化合物を橙色ゴム状物として生成した(1.49g、59%)。

Step 1: 3- (2,4-dimethoxybenzyl) -6,6-dimethyl-3-azabicyclo [3.1.0] Hexane-2,4-dione
THF (5 mL) of 2,4-dimethoxybenzylamine (1.45 g, 8.67 mmol) and 6,6-dimethyl-3-oxabicyclo [3.1.0] hexane-2,4-dione (1.21 g, 8.67 mmol) The solution was added dropwise at 0 ° C. The semi-solid mixture was heated to 90 ° C. to remove THF and the slowly melted solid as a mixture was heated to 180 ° C for 2h. The solution was cooled to -60 ° C and poured into ice-cooled DIPE to form a rubbery substance. This was separated and evaporated to give the title compound as an orange rubber (1.49 g, 59%).

Step 2: 3- (2,4-dimethoxybenzyl) -6,6-dimethyl-3-azabicyclo [3.1.0] hexane
Follow Method B from 3- (2,4-dimethoxybenzyl) -3-azabicyclo [3.1.0] hexane-2,4-dione (1.49 g, 5.15 mmol). The reaction was refluxed for 2 h and post-treated in the usual manner. As a result, the title compound was obtained as a pale yellow rubbery substance (1.31 g). The product was used in the next step without further purification.

Step 3: 6,6-dimethyl-3-azabicyclo [3.1.0] hexane hydrochloride
3- (2,4-dimethoxybenzyl) -6,6-dimethyl-3-azabicyclo [3.1.0] hexane (1.0 g, 3.83 mmol) was dissolved in methanol (50 mL) and acetic acid (5 mL), followed by 10% Pd / C (1.0 g) was added. The mixture was shaken in a hydrogen gas atmosphere (5 bar) at room temperature for 18 h. The reaction mixture is then filtered through Celite, acidified with 4N HCl in dioxane (5 mL) and concentrated to produce the title compound as a pale pink solid (1.0 g), which further comprises. Used in the next step without purification.

Step 4: Carbamate with tert-butyl ((2R) -1- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) -1-oxopropan-2-yl)
Method from (R) -2-((tert-butoxycarbonyl) amino) propanoic acid (659 mg, 3.48 mmol) and 6,6-dimethyl-3-azabicyclo [3.1.0] hexane hydrochloride (1.0 g, 3.83 mmol) Follow A. The title compound was obtained as a pale yellow rubbery substance (837 mg, 84%). The product was used in the next step without further purification.

Step 5: tert-Butyl ((2R) -1- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) carbamate
Method from tert-butyl ((2R) -1- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) -1-oxopropan-2-yl) carbamate (837 mg, 2.96 mmol) Follow B. The mixture was purified by passing it through an SCX cartridge (MeOH: eluted with 7M NH ₃ (9: 1) in MeOH). This gave the title compound as a pale yellow rubbery substance (525 mg, 66%).

Step 6: (2R) -1- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) propan-2-amine hydrochloride
From tert-butyl ((2R) -1- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) carbamate (525 mg, 1.96 mmol) according to Method C, the title The compound was obtained as an orange solid (900 mg,> 100%). It was used in the next step without further purification.

Step 7: N-((2R) -1- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide
From 4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (459 mg, 1.78 mmol) according to method A, (2R) -1- (6,6-dimethyl) -3-Azabicyclo [3.1.0] Hexane-3-yl) Propane-2-amine hydrochloride (900 mg, 1.95 mmol) and DIPEA (1.6 mL, 8.91 mmol) were added and the mixture was stirred for 18 h. The mixture was washed with water, passed through a phase separation cartridge and concentrated to produce a crude product. The residue was purified by preparative-HPLC to produce the title compound as an off-white solid (138 mg). LCMS (ES +) 409 (M + H) ⁺ , RT 4.53 minutes (analysis method 1); ^{1 1} H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.33 (1H, d, J = 8.3 Hz), 8.15 (2H, d, J = 8.7 Hz), 8.03 (2H, d, J = 8.7 Hz), 4.13 --4.04 (1H, m), 2.88 (2H, dd, J = 9.2, 24.6 Hz), 2.63 --2.54 ( 3H, m), 2.40 (1H, dd, J = 7.0, 11.7 Hz), 1.14 --1.10 (8H, m), 0.92 (3H, s).

[Example 23]
(2S) -1-((R) -2- (3-Fluoro-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl) -2- Methylpyrrolidine-1-iamformate

ステップ1:(Z)-3-フルオロ-4-(N'-ヒドロキシカルバムイミドイル)安息香酸
4-シアノ-3-フルオロ安息香酸(2.00g、12.1mmol)のEtOH(30mL)撹拌溶液に、NH₂OH.HCl(1.18g、17.0mmol)及びKOH(2.03g、36.3mmol)を加えた。混合物を、室温で17h撹拌し、次いで、1M HCl_(aq)で中和し、EtOAc(3×25mL)中で抽出した。合わせた有機物を、乾燥し(MgSO₄)、濃縮して、標題化合物を黄色油状物として得、これをさらには精製せずに進行させた。

Step 1: (Z) -3-fluoro-4- (N'-hydroxycarbamimideyl) benzoic acid
NH ₂ OH. HCl (1.18 g, 17.0 mmol) and KOH (2.03 g, 36.3 mmol) were added to a stirred solution of 4-cyano-3-fluorobenzoic acid (2.00 g, 12.1 mmol) in EtOH (30 mL). The mixture was stirred at room temperature for 17 h, then neutralized with 1M HCl _(aq) and extracted in EtOAc (3 x 25 mL). The combined organics were dried (DDL ₄ ) and concentrated to give the title compound as a yellow oil, which was allowed to proceed without further purification.

Step 2: 3-Fluoro-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid
TFAA (2.50 mL, 18.2 mmol) was added to a stirred solution of (Z) -3-fluoro-4- (N'-hydroxycarbamimideyl) benzoic acid (12.1 mmol) in THF (30 mL). The mixture was stirred for 3 h, then acidified to pH 4 with 1M HCl _(aq) , then poured into ice-water and extracted into EtOAc (3 x 30 mL). The combined organic matter was dried (DDL ₄ ) and concentrated. Purification by flash column chromatography (gradient elution i-hex [+ 3% AcOH] to i-hex: EtOAc [+ 3% AcOH] 4: 1) gave the title compound as an off-white solid (150 mg, 4). % (2 steps)). LCMS (ES +) 277 (M + H) ⁺ .

Step 3: (2S) -1-((R) -2-(3-fluoro-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl) -2-Methylpyrrolidine-1-Iumformate
Method A from 3-fluoro-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzoic acid (75 mg, 0.27 mmol) and intermediate 2 (59 mg, 0.41 mmol) Follow. Preparative-purification by HPLC gave the title compound as a yellow solid (39 mg, 32%). LCMS (ES +) 447 (M + H) ⁺ , RT 2.74 minutes (analysis method 1). ¹ H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 8.55 (1H, d, J = 8.2 Hz), 8.21 --8.17 (2H, m), 7.95 --7.91 (2H, m), 4.19 --4.09 (1H, m), 3.13 (1H, ddd, J = 4.1, 7.2, 8.9 Hz), 2.74 (1H, dd, J = 9.3, 11.7 Hz), 2.42 --2.34 (1H, m), 2.28 (1H, dd, J = 5.7, 11.3 Hz), 2.20 (1H, q, J = 8.7 Hz), 1.93 --1.83 (1H, m), 1.73 --1.63 (2H, m), 1.39 --1.25 (1H, m), 1.19 (3H, d, J = 6.7 Hz), 1.05 (3H, d, J = 6.0 Hz).

[Example 24]
N-((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) -5- (5- (trifluoromethyl) -1,2,4-oxadiazole -3-Il) Picoline amide

ステップ1:(Z)-5-(N'-ヒドロキシカルバムイミドイル)ピコリン酸
5-シアノピコリン酸(1.51g、10.2mmol)のEtOH(30mL)撹拌溶液に、NH₂OH.HCl(999mg、14.3mmol)及びKOH(1.71g、30.6mmol)を加えた。混合物を、室温で72h撹拌し、次いで、1M HCl_(aq)で中和した。得られた沈殿物を、真空濾過により収集し、H₂O及びEtOHで洗浄し、減圧下で乾燥して、標題化合物を白色固体として得た(1.21g、63%)。

Step 1: (Z) -5- (N'-hydroxycarbamimideyl) picolinic acid
NH ₂ OH. HCl (999 mg, 14.3 mmol) and KOH (1.71 g, 30.6 mmol) were added to a stirred solution of 5-cyanopicolinic acid (1.51 g, 10.2 mmol) in EtOH (30 mL). The mixture was stirred at room temperature for 72 h and then neutralized with 1M HCl _(aq) . The resulting precipitate was collected by vacuum filtration, washed with H ₂ O and Et OH and dried under reduced pressure to give the title compound as a white solid (1.21 g, 63%).

Step 2: 5- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) picolinic acid
TFAA (1.35 mL, 9.71 mmol) was added to a stirred solution of (Z) -5- (N'-hydroxycarbamimideyl) picolinic acid (1.21 g, 6.47 mmol) in THF (20 mL). The mixture was stirred at room temperature for 17 h, then poured into ice-water, acidified to pH 4 with 1M HCl _(aq) and then extracted into EtOAc (3 x 30 mL). The combined organic matter was dried (DDL ₄ ) and concentrated. The residue was dissolved in DCM / MeOH (10 mL, 1: 1) and the insoluble solid was collected by vacuum filtration to give the title compound as an off-white solid (593 mg, 35%). LCMS (ES +) 260 (M + H) ⁺ .

Step 3: N-((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) -5- (5- (trifluoromethyl) -1,2,4- Oxadiazole-3-yl) picoline amide
Follow Method A from 5- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) picolinic acid (200 mg, 0.77 mmol) and intermediate 2 (166 mg, 1.16 mmol). The title is by purifying by reverse phase chromatography (gradient elution, 5-95% MeCN in 0.1% formic acid) and then passing through an SCX cartridge (MeOH: eluted with 7M NH ₃ (9: 1) in MeOH). The compound was obtained as an orange rubbery substance (72 mg, 24%). LCMS (ES +) 384 (M + H) ⁺ , RT 3.92 minutes (analysis method 2). ¹ H NMR δ (ppm) (400 MHz, DMSO-d ₆ ) 9.25 (1H, d, J = 1.8 Hz), 8.73 (1H, d, J = 8.7 Hz), 8.64 (1H, dd, J = 2.1, 8.2 Hz), 8.26 (1H, d, J = 8.2 Hz), 4.19 --4.09 (1H, m), 3.15 --3.07 ( 1H, m), 2.82 (1H, dd, J = 9.0, 11.8 Hz), 2.37-2.28 (1H, m), 2.23 (1H, dd, J = 5.1, 10.9 Hz), 2.16 (1H, q, J = 8.7 Hz), 1.91 --1.90 (1H, m), 1.71 --1.61 (2H, m), 1.34 --1.23 (1H, m), 1.21 (3H, d, J = 6.5 Hz), 1.02 (3H, d, J) = 6.0 Hz).
Table of examples

[Example 25]
Analysis of inhibition of HDAC4 by class IIa histone deacetylase (HDAC) inhibitors.
Efficacy of class IIa histone deacetylase (HDAC) inhibitors is quantified by measuring histone deacetylase 4 (HDAC4) catalytic domain enzyme activity using the fluorescent substrate, Boc-Lys (TFA) -AMC. did. The substrate was deacetylated to Boc-Lys-AMC with HDAC4. When cleaved by trypsin, it releases fluorophore AMC from the deacetylated substrate. Fluorescence of the sample was directly associated with histone deacetylase activity in the sample.

The HDAC inhibitor compound is continuously diluted. HDAC inhibitor and control reference compound (1- (5-(3-((4- (1,3,4-oxadiazole-2-yl) phenoxy) methyl) -1,2,4-oxadiazole) -5-Il) Thiophen-2-yl) -2,2,2-trifluoroetanone) serially diluted, first lyophilized compound in 100% dimethyl sulfoxide (DMSO) to a final concentration of 10 mM. Made by turbidity. A stock of 60 μL aliquots of 10 mM compound in DMSO was prepared and stored at -20 ° C. From 1 stock alicot of each compound to be tested, and 1 stock alicot of the reference compound, 16-point serial dilutions, 16-point serial dilutions, 125 μL 16-channel Matrix multi-channel pipette (Matrix) according to Table 1. Prepared using Technologies Ltd).

2 μL (200 ×) of each diluted solution and each control (complete activity: 100% DMSO alone or complete inhibition 1 mM) into a V-bottomed polypropylene 384-well compound plate, Bravo (Agilent 384). Well head) or 12.5 μL 16-channel Matrix Multichannel Pipette (Matrix Technologies Ltd.) was used for stamping. Each well with a 200 × compound solution was placed in 38 μL assay buffer + DMSO (10.5% DMSO at pH 8.0 and equilibrated to room temperature, 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl and It was diluted 1:20 by adding 0.9 mM MgCl ₂ ).

Prepare the HDAC4 catalytic domain enzyme (0.2 μg / mL). The HDAC4 catalytic domain enzyme was a human catalytic domain HDAC4 protein (amino acid 648-1032) produced by BioFocus with a C-terminal 6 × histidine tag. 0.2 dilute standard solution of enzyme in assay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl and 1 mM MgCl ₂ at pH 8 and equilibrated to room temperature) just prior to adding the enzyme to the assay. Prepared from 500 μg / mL stock aliquots (thawed on ice) of HDAC4 catalytic domain diluted to μg / mL.

Prepare a 5 × (50 μM) Boc-Lys (TFA) -AMC substrate. A 5x (50 μM) substrate was prepared just prior to addition to the assay. 1 mM substrate stock, 100 mM Boc-Lys (Tfa) -AMC solution in DMSO added dropwise to assay buffer (equilibrium to room temperature) while vortexing slowly to prevent precipitation. It was made by diluting to 1: 100. 5 × substrate was prepared by adding a 1 mM substrate solution to the assay buffer (equilibrium to room temperature) in drops and vortexing slowly to prevent precipitation during that time and diluting to 1:20. ..

Prepare a 3x (30 μM) developing agent / stop solution. Just before adding the 3 × (30 μM) developing agent / stop solution to the plate, dilute the stock of 25 mg / mL trypsin solution (PAA Laboratories Ltd.) of 10 mM reference compound equilibrated to room temperature to 1: 333. Prepared by

Assay. 5 μL of each solution of the compound diluted 1:20 from the above to a clear-bottomed, black, 384-well assay plate using Bravo or Janus (a 384-well MDT head from Perkin Elmer). I moved it. Using a 16-channel Matrix Multichannel Pipette, 35 μL of a diluted standard solution of HDAC4 catalytic domain enzyme (0.2 μg / mL in assay buffer) was transferred to the assay plate. The assay was then initiated by adding 10 μL of 5 × (50 μM) substrate to the assay plate using either Bravo, Janus or a 16 channel Matrix Multichannel Pipette. The assay plate was then shaken on an orbital shaker at 900 rpm (rotations per minute) for 2 minutes. The plate was then incubated at 37 ° C for 15 minutes. The reaction was stopped by adding 25 μL of 3 × (30 μM) developing agent / stop solution to the assay plate using either Bravo, Janus or a 16-channel Matrix Multichannel Pipette. The assay plate was then shaken on an orbital shaker at 1200 rpm for 5 minutes. The assay plate was then incubated in a tissue culture incubator at 37 ° C. for 1 hour. Finally, fluorescence was measured using PerkinElmer EnVision in top read mode (excitation: 355 nm, emission: 460 nm).

[Example 26]
Analysis of inhibition of HDAC5 by class IIa histone deacetylase (HDAC) inhibitors.
The effectiveness of class IIa histone deacetylase (HDAC) inhibitors is quantified by measuring histone deacetylase 5 (HDAC5) enzyme activity using the fluorescence-generating substrate Boc-Lys (TFA) -AMC. The substrate is deacetylated to Boc-Lys-AMC by HDAC5. Cleavage with trypsin results in the release of fluorophore AMC from the deacetylated substrate. Fluorescence of a sample is directly involved in histone deacetylase activity in the sample.

The HDAC inhibitor compound is diluted stepwise. HDAC inhibitor and control reference compound (1- (5- (3-((4- (1,3,4-oxadiazole-2-yl) phenoxy) methyl) -1,2,4-oxadiazole) A serial dilution of -5-yl) thiophen-2-yl) -2,2,2-trifluoroetanone) is first resuspended in lyophilized compound in 100% DMSO to a final concentration of 10 mM. By doing so. A stock of 60 μL aliquots of 10 mM compound in DMSO is prepared and stored at -20 ° C. From each compound to be tested, and one stock aliquot of the reference compound, a 16-point serial dilution is prepared using 125 μL of 16-channel Matrix Multichannel Pipette according to Table 1.

Bravo, Janus or 12.5 μL of 2 μL (200 ×) of each diluted solution and each control (complete activity: 100% DMSO alone or complete inhibition 1 mM) into a 384-well compound plate of polypropylene with a V-bottom. Stamp using one of the 16-channel Matrix Multichannel Pipette. Each well with 2 μL of a 200 × stamped compound solution was placed in 38 μL assay buffer + DMSO (10.5% DMSO at pH 8.0 and equilibrated to 37 ° C., 45 mM Tris-HCl, 123 mM). Dilute to 1:20 by adding NaCl, 2.4 mM KCl and 0.9 mM MgCl ₂ l).

Prepare the HDAC5 catalytic domain enzyme (0.57 μg / mL). The HDAC5 catalytic domain enzyme is a human HDAC5 catalytic domain (GenBank Accession No. NM_001015053) amino acid 657-1123 with a C-terminal His tag and can be obtained from BPS BioScience. The protein is 51 kDa and is expressed in the baculovirus expression system. Dilution of enzyme The standard solution was diluted to 0.57 μg / mL with an assay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl and 1 mM MgCl ₂ at pH 8 and equilibrated to 37 ° C.). Prepare from a 1.65 mg / mL stock aliquot (thawed on ice) of the HDAC5 catalytic domain just before adding the enzyme to the assay.

Prepare a 5 × (40 μM) Boc-Lys (TFA) -AMC substrate. A 5x (40 μM) substrate is prepared just prior to addition to the assay. A 5 × substrate was added dropwise to the assay buffer (equilibrium to 37 ° C.) a solution of 100 mM Boc-Lys (TFA) -AMC in DMSO while vortexing slowly to prevent precipitation. Prepare by diluting to 1: 2500.

Prepare a 3x (30 μM) developing agent / stop solution. Prepared by diluting a stock of 25 mg / mL trypsin solution of 10 mM reference compound equilibrated to 37 ° C. to 1: 333 just prior to adding 3 × (30 μM) developing agent / stop solution to the plate. To do.

Assay. Transfer 5 μL of each solution of inhibitor compound and control diluted 1:20 from above to a clear-bottomed, black, 384-well assay plate using Bravo or Janus. Using a 16-channel Matrix Multichannel Pipette, transfer 35 μL of a diluted standard solution of HDAC5 catalytic domain enzyme (0.57 μg / mL in assay buffer) to the assay plate. The assay is then initiated by adding 10 μL of 5 × (40 μM) substrate to the assay plate using either Bravo, Janus or a 16 channel Matrix Multichannel Pipette. The assay plate is then shaken on an orbital shaker at 900 rpm for 1 minute. The plate is then incubated at 37 ° C for 15 minutes. Stop the reaction by adding 25 μL of 3 × (30 μM) developing agent / stop solution to the assay plate using either Bravo, Janus or a 16-channel Matrix Multichannel Pipette. The assay plate is then shaken on an orbital shaker at 900 rpm for 2 minutes. The assay plate is then incubated in a tissue culture incubator at 37 ° C. for 1 hour, followed by shaking on an orbital shaker at maximum rpm for 1 minute, followed by reading on EnVision. Finally, fluorescence is measured using PerkinElmer EnVision in top read mode (excitation: 355 nm, emission: 460 nm).

[Example 27]
Analysis of HDAC7 Inhibition by Class IIa Histone Deacetylase (HDAC) Inhibitors The effectiveness of class IIa histone deacetylase (HDAC) inhibitors, histone deacetylase 7 (HDAC7) enzyme activity, fluorescence generation substrate Boc-Lys (TFA)-Quantify by measuring using AMC. The substrate is deacetylated to Boc-Lys-AMC by HDAC7. Cleavage with trypsin results in the release of fluorophore AMC from the deacetylated substrate. Fluorescence of a sample is directly involved in histone deacetylase activity in the sample.

The HDAC inhibitor compound is diluted stepwise. HDAC inhibitor and control reference compound (1- (5- (3-((4- (1,3,4-oxadiazole-2-yl) phenoxy) methyl) -1,2,4-oxadi A serial dilution of azole-5-yl) thiophen-2-yl) -2,2,2-trifluoroetanone) was first resuspended in lyophilized compound in 100% DMSO to a final concentration of 10 mM. It is produced by making it. A stock of 60 μL aliquots of 10 mM compound in DMSO is prepared and stored at -20 ° C. From each compound to be tested, and one stock aliquot of the reference compound, a 16-point serial dilution is prepared using 125 μL of 16-channel Matrix Multichannel Pipette according to Table 1.

Bravo, Janus or 12.5 μL of 2 μL (200 ×) of each diluted solution and each control (complete activity: 100% DMSO alone or complete inhibition 1 mM) into a 384-well compound plate of polypropylene with a V-bottom. Stamp using one of the 16-channel Matrix Multichannel Pipetter. Each well with a 200 × compound solution was placed in 38 μL assay buffer + DMSO (10.5% DMSO at pH 8.0 and equilibrated to 37 ° C., 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM KCl. And 0.9 mM Mg Cl ₂ ) to dilute to 1:20.

Prepare the HDAC7 enzyme (71 ng / mL). The HDAC7 enzyme is a human HDAC7 (GenBank Accession No. AY302468) amino acid 518-terminal with an N-terminal glutathione S-transfer (GST) tag and can be obtained from BPS BioScience. The protein is 78 kDa and is expressed in the baculovirus expression system. Diluted standard solution of enzyme diluted to 71 ng / mL with assay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl and 1 mM MgCl ₂ at pH 8 and equilibrated to 37 ° C), HDAC7 Prepare from 0.5 mg / mL stock aliquots (thawed on ice) of 0.5 mg / mL just prior to adding the enzyme to the assay.

Prepare a 5 × (50 μM) Boc-Lys (TFA) -AMC substrate. A 5x (50 μM) substrate is prepared just prior to addition to the assay. A 5 × substrate was added dropwise to the assay buffer (equilibrium to 37 ° C.) a solution of 100 mM Boc-Lys (TFA) -AMC in DMSO while vortexing slowly to prevent precipitation. Prepare by diluting to 1: 2000.

Prepare a 3x (30 μM) developing agent / stop solution. Prepared by diluting a stock of 25 mg / mL trypsin solution of 10 mM reference compound equilibrated to 37 ° C. to 1: 333 just prior to adding 3 × (30 μM) developing agent / stop solution to the plate. To do.

Assay. Transfer 5 μL of each solution of the compound diluted 1:20 from above to a clear-bottomed, black, 384-well assay plate using Bravo or Janus. Using a 16-channel Matrix Multichannel Pipette, transfer 35 μL of a diluted standard solution of HDAC7 enzyme (71 ng / mL in assay buffer) to the assay plate. The assay is then initiated by adding 10 μL of 5 × (50 μM) substrate to the assay plate using either Bravo, Janus or a 16 channel Matrix Multichannel Pipette. The assay plate is then shaken on an orbital shaker at 900 rpm for 1 minute. The plate is then incubated at 37 ° C for 15 minutes. Stop the reaction by adding 25 μL of 3 × (30 μM) developing agent / stop solution to the assay plate using either Bravo, Janus or a 16-channel Matrix Multichannel Pipette. The assay plate is then shaken on an orbital shaker at 900 rpm for 2 minutes. The assay plate is then incubated in a tissue culture incubator at 37 ° C. for 1 hour, followed by shaking on an orbital shaker at maximum rpm for 1 minute. Finally, fluorescence is measured using PerkinElmer EnVision in top read mode (excitation: 355 nm, emission: 460 nm).

[Example 28]
Analysis of HDAC9 Inhibition by Class IIa Histone Deacetylase (HDAC) Inhibitors Fluorescence Generation Substrate Boc-Lys The Effectiveness of Class IIa Histone Deacetylase (HDAC) Inhibitors, Histone Deacetylase 9 (HDAC9) Enzyme Activity (Quantified by measurement using TFA-AMC. Substrate is deacetylated to Boc-Lys-AMC by HDAC9. Cleavage with trypsine releases fluorophore AMC from the deacetylated substrate. The result is that the fluorescence of the sample is directly involved in the histone deacetylase activity in the sample.

The HDAC inhibitor compound is diluted stepwise. HDAC inhibitor compound and control reference compound (1- (5- (3-((4- (1,3,4-oxadiazole-2-yl) phenoxy) methyl) -1,2,4-oxadi A serial dilution of azole-5-yl) thiophen-2-yl) -2,2,2-trifluoroetanone) was first resuspended in lyophilized compound in 100% DMSO to a final concentration of 10 mM. It is produced by making it. A stock of 60 μL aliquots of 10 mM compound in DMSO is prepared and stored at -20 ° C. From each compound to be tested, and one stock aliquot of the reference compound, a 16-point serial dilution is prepared using 125 μL of 16-channel Matrix Multichannel Pipette according to Table 1.

Bravo, Janus or 12.5 μL of 2 μL (200 ×) of each diluted solution and each control (complete activity: 100% DMSO alone or complete inhibition 1 mM) into a 384-well compound plate of polypropylene with a V-bottom. Stamp using one of the 16-channel Matrix Multichannel Pipette. Each well with a stamped 200 × compound solution was placed in 38 μL assay buffer + DMSO (10.5% DMSO at pH 8.0 and equilibrated to 37 ° C., 45 mM Tris-HCl, 123 mM NaCl, 2.4 mM). Dilute to 1:20 by adding KCl and 0.9 mM MgCl ₂ ).

Prepare HDAC9 enzyme (0.57 μg / mL). The HDAC9 enzyme is a human HDAC9 (GenBank Accession No. NM_178423) amino acid 604-1066 with a C-terminal His tag and can be obtained from BPS BioScience. The protein is 50.7 kDa and is expressed in the baculovirus expression system. Dilution standard solution of enzyme was diluted to 0.57 μg / mL with assay buffer (50 mM Tris-HCl, 137 mM NaCl, 2.7 mM KCl and 1 mM MgCl ₂ at pH 8 and equilibrated to 37 ° C). Prepare from 0.5 mg / mL stock aliquots of HDAC9 (thawed on ice) just before adding the enzyme to the assay.

Prepare a 5 × (125 μM) Boc-Lys (TFA) -AMC substrate. A 5x (125 μM) substrate is prepared just prior to addition to the assay. A 5 × substrate was added dropwise to the assay buffer (equilibrium to 37 ° C.) a solution of 100 mM Boc-Lys (Tfa) -AMC in DMSO while vortexing slowly to prevent precipitation. Prepare by diluting to 1: 800.

Prepare a 3x (30 μM) developing agent / stop solution. Prepared by diluting a stock of 25 mg / mL trypsin solution of 10 mM reference compound equilibrated to 37 ° C. to 1: 333 just prior to adding 3 × (30 μM) developing agent / stop solution to the plate. To do.

Assay. Transfer 5 μL of each solution of the compound diluted 1:20 from above to a clear-bottomed, black, 384-well assay plate using Bravo or Janus. Using a 16-channel Matrix Multichannel Pipette, transfer 35 μL of a diluted standard solution of HDAC9 enzyme (0.57 μg / mL in assay buffer) to the assay plate. The assay is then initiated by adding 10 μL of 5 × (125 μM) substrate to the assay plate using either Bravo, Janus or a 16 channel Matrix Multichannel Pipette. The assay plate is then shaken on an orbital shaker at 900 rpm for 1 minute. The plate is then incubated at 37 ° C for 15 minutes. Stop the reaction by adding 25 μL of 3 × (30 μM) developing agent / stop solution to the assay plate using either Bravo, Janus or a 16-channel Matrix Multichannel Pipette. The assay plate is then shaken on an orbital shaker at 900 rpm for 2 minutes. The assay plate is then incubated in a tissue culture incubator at 37 ° C. for 1 hour, followed by shaking on an orbital shaker at maximum rpm for 1 minute, followed by reading on EnVision. Finally, fluorescence is measured using PerkinElmer EnVision in top read mode (excitation: 355 nm, emission: 460 nm).

[Example 29]
Analysis of inhibition of cellular class IIa HDAC activity by class IIa histone deacetylase (HDAC) inhibitors; cellular (Lys-TFA) substrate.
The efficacy of class IIa histone deacetylase (HDAC) inhibitors was quantified by measuring the enzymatic activity of cellular histone deacetylase using the fluorescent substrate Boc-Lys (TFA) -AMC. After penetration into Jurkat E6-1 cells, the substrate was deacetylated to Boc-Lys-AMC. After cell lysis and cleavage with trypsin, fluorophore AMC was released only from the deacetylated substrate. Fluorescence of the sample was directly involved in histone deacetylase activity in the sample.

Jurkat E6.1 Cell culture and plating. Jurkat E6.1 cells were cultured according to standard cell culture protocols in Jurkat E6.1 growth medium (RPMI without phenol red, 10% FBS, 10 mM HEPES and 1 mM sodium pyruvate). Jurkat E6.1 cells were counted using a Coulter Counter and resuspended in Jurkat E6.1 growth medium at a concentration of 75,000 cells per 35 μL. 35 μL or 75,000 cells were seeded in Greiner microtiter assay plates. The plates were then incubated at 37 ° C. and 5% CO ₂ while preparing the other assay components.

The HDAC inhibitor compound is diluted stepwise. HDAC inhibitor and control reference compound (1- (5- (3-((4- (1,3,4-oxadiazole-2-yl) phenoxy) methyl) -1,2,4-oxadiazole) A serial dilution of -5-yl) thiophen-2-yl) -2,2,2-trifluoroetanone) is first resuspended in lyophilized compound in 100% DMSO to a final concentration of 10 mM. By doing so. A stock of 70 μL aliquots of 10 mM compound in DMSO was prepared and stored at -20 ° C. From 1 stock aliquot of each compound and reference compound tested, 16 point serial dilutions were prepared using 125 μL of 16 channel Matrix Multichannel Pipette according to Table 1.

Bravo, Janus or 12.5 μL of 2 μL (200 ×) of each diluted solution and each control (complete activity: 100% DMSO alone or complete inhibition 1 mM) into a 384-well compound plate of polypropylene with a V-bottom. Stamped using one of the 16-channel Matrix Multichannel Pipette. Each well with a 200 × compound solution was placed in 38 μL of Jurkat assay buffer + DMSO (9.5% DMSO equilibrated to room temperature, RPMI without phenol red, 0.09% FBS, 9 mM HEPES and 0.9 mM pyruvate). Dilute to 1:20 by adding (sodium).

Prepare a 5 × (500 μM) Boc-Lys (TFA) -AMC substrate. A 5x (500 μM) substrate was prepared just prior to addition to the assay. 5 × substrate, 100 mM Boc-Lys (TFA) -AMC solution in DMSO instills it in the Jurkat assay medium (equilibrium to 37 ° C, RPMI without phenol red, 0.1% FBS, 10 mM HEPES) And 1 mM sodium pyruvate), meanwhile, prepared by slow vortexing and diluting to 1: 200 to prevent precipitation.

Prepare a 3x dissolution buffer. 10 mL of 3x lysis buffer, 3x stock lysis buffer (equilibrium to room temperature, 50 mM Tris-HCl, pH 8.0, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl ₂ , 1% Nonidet P40 Prepared with 8.8 ml of Substitute) and 1.2 mL of 3 mg / mL trypsin equilibrated to room temperature.
Assay. 5 μL of each 1:20 diluted solution from the above was transferred using Bravo to an assay plate on the Greiner microtiter with 75,000 cells per well. The cells were then incubated at 37 ° C. and 5% CO _{2 for} 2 hours. The assay was then initiated by adding 10 μL of 5 × (500 μM) substrate to the assay plate using either Bravo or a 16-channel Matrix Multichannel Pipette. The cells were then incubated at 37 ° C. and 5% CO _{2 for} 3 hours. Twenty-five μL of 3x lysis buffer was then added to each well using either a 125 μL 16-channel pipette or Bravo. The assay plates were then incubated overnight (15-16 hours) at 37 ° C. and 5% CO ₂ . The next day, the plate was shaken on an orbital shaker at 900 rpm for 1 minute. Finally, top read fluorescence (excitation: 355 nm, emission: 460 nm) was measured using PerkinElmer EnVision.

[Example 30]
Analysis of inhibition of cell class I HDAC activity by class IIa histone deacetylase (HDAC) inhibitors; cellular (Lys-Ac) substrate.
Class IIa histone deacetylase (HDAC) inhibitor class I HDAC activity was quantified by measuring the enzymatic activity of cellular histone deacetylase using the fluorescent substrate Boc-Lys (Ac) -AMC. .. This was done according to the procedure in Example 29, using the Boc-Lys (Ac) -AMC substrate instead of Boc-Lys (TFA) -AMC.

The following compounds were synthesized and tested using a synthetic method similar to that described above and the assay protocol described above. Examples 1, 17, and 23 in the table below are shown as formates, but free bases may be used in the assay in a corresponding manner.

参照文献:
1)Bioorganic & Medicinal Chemistry Letters 17巻(2007年)6476〜6480

References:
1) Bioorganic & Medicinal Chemistry Letters Volume 17 (2007) 6476-6480

[式中、
Wは、N又はCR⁵であり;Xは、N又はCR⁶であり;Yは、N又はCR⁷であり;Zは、N又はCR⁸であり;ただし、W、X、Y、及びZのうち2個以下は、Nであり;
R¹は、H及びC₁〜C₃アルキルから選択され;
R²は、C₁〜C₂ハロアルキル又は3若しくは4員のシクロアルキルで任意選択で置換されているC₂〜C₃アルキレンであり;
R³及びR⁴は、これらが結合している窒素原子と一緒になって、
4、5、6、若しくは7員の複素単環式基、又は
6、7、8、9、若しくは10員の複素二環式基を形成し、
それらのそれぞれは、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換され、ここでアリール及びヘテロアリールは、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換され、
ただし、R³及びR⁴が、これらが結合している窒素原子と一緒になって、5又は6員の複素単環式基を形成する場合、
i)R²は、C₁〜C₂ハロアルキル又は3若しくは4員のシクロアルキルで置換されているC₂〜C₃アルキレンである、又は
ii)R⁸は、ハロ若しくはC₁〜C₃アルキルである、又は
iii)5若しくは6員の複素単環式基は、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3若しくは4員のシクロアルコキシ、3若しくは4員のシクロアルキル、3若しくは4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で置換され、ここでアリール及びヘテロアリールは、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換され;
R⁵、R⁶、R⁷及びR⁸は、H、C₁〜C₄アルキル、C₁〜C₄ハロアルキル、及びハロからそれぞれ独立に選択される]
の化合物又はその薬学的に許容される塩、光学異性体若しくは光学異性体の混合物。
（付記２）
式Iの化合物が、式II

の化合物である、付記1に記載の化合物又はその薬学的に許容される塩。
（付記３）
R²が、3又は4員のシクロアルキルで任意選択で置換されているC₂〜C₃アルキレンである、付記1又は2に記載の化合物又はその薬学的に許容される塩。
（付記４）
式Iの化合物が、式III

の化合物である、付記3に記載の化合物又はその薬学的に許容される塩。
（付記５）
R⁶がHである、付記1から4のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記６）
式Iの化合物が、式V

の化合物である、付記1に記載の化合物又はその薬学的に許容される塩。
（付記７）
R²が、3又は4員のシクロアルキルで任意選択で置換されているC₂〜C₃アルキレンである、付記6に記載の化合物又はその薬学的に許容される塩。
（付記８）
式Iの化合物が、式VI

の化合物である、付記7に記載の化合物又はその薬学的に許容される塩。
（付記９）
R⁵がHである、付記1から8のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記１０）
R⁷がHである、付記1から9のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記１１）
R⁸が、H、ハロ、及びメチルから選択される、付記1から10のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記１２）
R¹が、H及びメチルから選択される、付記1から11のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記１３）
R¹がHである、付記12に記載の化合物又はその薬学的に許容される塩。
（付記１４）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている4又は7員の複素単環式基を形成し、ここでアリール及びヘテロアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記1から13のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記１５）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、
3-フェニルアゼチジン-1-イル、及び
アゼパン-1-イル
から選択される4又は7員の複素単環式基を形成する、付記14に記載の化合物又はその薬学的に許容される塩。
（付記１６）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている5又は6員の複素単環式基を形成し、ここでアリール及びヘテロアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換され、
R²が、C₁〜C₂ハロアルキル又は3若しくは4員のシクロアルキルで置換されているC₂〜C₃アルキレンである、付記1から13のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記１７）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、アリール、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている5又は6員の複素単環式基を形成し、ここでアリール及びヘテロアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記16に記載の化合物又はその薬学的に許容される塩。
（付記１８）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、及びアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている5又は6員の複素単環式基を形成し、ここでアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記17に記載の化合物又はその薬学的に許容される塩。
（付記１９）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、及びフェニルからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている5又は6員の複素単環式基を形成し、ここでフェニルが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記18に記載の化合物又はその薬学的に許容される塩。
（付記２０）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、メチル、ジフルオロメトキシ、及びフェニルからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている5又は6員の複素単環式基を形成する、付記19に記載の化合物又はその薬学的に許容される塩。
（付記２１）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、ピロリジン-1-イル、及びピペリジン-1-イルから選択される5又は6員の複素単環式基を形成し、そのそれぞれが、メチル、ジフルオロメトキシ、及びフェニルから選択される1つの置換基で任意選択で置換されている、付記20に記載の化合物又はその薬学的に許容される塩。
（付記２２）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、
ピロリジン-1-イル、
2-メチル-ピロリジン-1-イル、及び
3-(ジフルオロメトキシ)ピペリジン-1-イル
から選択される5又は6員の複素単環式基を形成する、付記21に記載の化合物又はその薬学的に許容される塩。
（付記２３）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている5又は6員の複素単環式基を形成し、ここでアリール及びヘテロアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換され、
R⁸が、ハロ又はC₁〜C₃アルキルである、付記1から13のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記２４）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、アリール、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている5又は6員の複素単環式基を形成し、ここでアリール及びヘテロアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記23に記載の化合物又はその薬学的に許容される塩。
（付記２５）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、及びアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている5又は6員の複素単環式基を形成し、ここでアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記24に記載の化合物又はその薬学的に許容される塩。
（付記２６）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、及びフェニルからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている5又は6員の複素単環式基を形成し、ここでフェニルが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記25に記載の化合物又はその薬学的に許容される塩。
（付記２７）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、メチル、ジフルオロメトキシ、及びフェニルからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換されている5又は6員の複素単環式基を形成する、付記26に記載の化合物又はその薬学的に許容される塩。
（付記２８）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、ピロリジン-1-イル、及びピペリジン-1-イルから選択される5又は6員の複素単環式基を形成し、そのそれぞれが、メチル、ジフルオロメトキシ、及びフェニルから選択される1つの置換基で任意選択で置換されている、付記27に記載の化合物又はその薬学的に許容される塩。
（付記２９）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、
ピロリジン-1-イル、
2-メチル-ピロリジン-1-イル、及び
3-(ジフルオロメトキシ)ピペリジン-1-イル
から選択される、5又は6員の複素単環式基を形成する、付記28に記載の化合物又はその薬学的に許容される塩。
（付記３０）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で置換されている5又は6員の複素単環式基を形成し、ここでアリール及びヘテロアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記1から13のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記３１）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、及びアリールからそれぞれ独立に選択される1〜5つの置換基で置換されている5又は6員の複素単環式基を形成し、ここでアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記30に記載の化合物又はその薬学的に許容される塩。
（付記３２）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、及びフェニルからそれぞれ独立に選択される1〜5つの置換基で置換されている5又は6員の複素単環式基を形成し、ここでフェニルが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記31に記載の化合物又はその薬学的に許容される塩。
（付記３３）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、メチル、ジフルオロメトキシ、及びフェニルからそれぞれ独立に選択される1〜5つの置換基で置換されている5又は6員の複素単環式基を形成する、付記32に記載の化合物又はその薬学的に許容される塩。
（付記３４）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、ピロリジン-1-イル、及びピペリジン-1-イルから選択される5又は6員の複素単環式基を形成し、そのそれぞれが、メチル、ジフルオロメトキシ、及びフェニルから選択される1つの置換基で置換されている、付記33に記載の化合物又はその薬学的に許容される塩。
（付記３５）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、
2-メチル-ピロリジン-1-イル、及び
3-(ジフルオロメトキシ)ピペリジン-1-イル
から選択される、5又は6員の複素単環式基を形成する、付記34に記載の化合物又はその薬学的に許容される塩。
（付記３６）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、(2S)-メチル-ピロリジン-1-イルを形成する、付記1から13のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記３７）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、6、7、8、9、又は10員の複素二環式基を形成し、複素二環式基は、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換され、ここでアリール及びヘテロアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記1から13のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記３８）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、
1-アザスピロ[3.3]ヘプタン-1-イル、
3-アザビシクロ[3.1.0]ヘキサン-3-イル、
3-アザビシクロ[3.2.0]ヘプタン-3-イル、
3-アザビシクロ[3.2.1]ヘプタン-3-イル、
3-アザビシクロ[3.2.1]オクタン-3-イル、
3,4-ジヒドロイソキノリン-2(1H)-イル、
3,4-ジヒドロ-2,7-ナフチリジン-2(1H)-イル、
5-アザスピロ[2.4]ヘプタン-5-イル、
5-アザスピロ[2.5]オクタン-5-イル、
6-アザスピロ[2.5]オクタン-6-イル、
1-アザスピロ[3.3]ヘプタン-1-イル、
6-アザビシクロ[3.2.0]ヘプタン-6-イル、
イソインドリン-2-イル、及び
オクタヒドロシクロペンタ[c]ピロール-2-イル
から選択される6、7、8、9、又は10員の複素二環式基を形成し、
そのそれぞれが、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、3又は4員のシクロアルコキシ、3又は4員のシクロアルキル、3又は4員のヘテロシクロアルキル、カルボキシ、アリール、シアノ、ハロ、及びヘテロアリールからそれぞれ独立に選択される1〜5つの置換基で任意選択で置換され、ここでアリール及びヘテロアリールが、C₁〜C₃アルキル、C₁〜C₃ハロアルキル、及びハロからそれぞれ独立に選択される1〜5つの置換基で任意選択でさらに置換されている、付記1から13のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記３９）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、
1-アザスピロ[3.3]ヘプタン-1-イル、
3-アザビシクロ[3.1.0]ヘキサン-3-イル、
3-アザビシクロ[3.2.0]ヘプタン-3-イル、
3-アザビシクロ[3.2.1]ヘプタン-3-イル、
3-アザビシクロ[3.2.1]オクタン-3-イル、
3,4-ジヒドロイソキノリン-2(1H)-イル、
3,4-ジヒドロ-2,7-ナフチリジン-2(1H)-イル、
5-アザスピロ[2.4]ヘプタン-5-イル、
5-アザスピロ[2.5]オクタン-5-イル、
6-アザスピロ[2.5]オクタン-6-イル、
1-アザスピロ[3.3]ヘプタン-1-イル、
6-アザビシクロ[3.2.0]ヘプタン-6-イル、
イソインドリン-2-イル、及び
オクタヒドロシクロペンタ[c]ピロール-2-イル
から選択される6、7、8、9、又は10員の複素二環式基を形成し、
そのそれぞれが、C₁〜C₃アルコキシ、C₁〜C₃アルキル、C₁〜C₃ハロアルコキシ、C₁〜C₃ハロアルキル、及びカルボキシからそれぞれ独立に選択される1つ又は2つの置換基で任意選択で置換されている、付記1から13のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記４０）
R³及びR⁴が、これらが結合している窒素原子と一緒になって、
1-アザスピロ[3.3]ヘプタン-1-イル、
3-アザビシクロ[3.1.0]ヘキサン-3-イル、
3-アザビシクロ[3.2.0]ヘプタン-3-イル、
3-アザビシクロ[3.2.1]ヘプタン-3-イル、
3-アザビシクロ[3.2.1]オクタン-3-イル、
3,4-ジヒドロイソキノリン-2(1H)-イル、
3,4-ジヒドロ-2,7-ナフチリジン-2(1H)-イル、
5-アザスピロ[2.4]ヘプタン-5-イル、
5-アザスピロ[2.5]オクタン-5-イル、
6-アザスピロ[2.5]オクタン-6-イル、
1-アザスピロ[3.3]ヘプタン-1-イル、
6-アザビシクロ[3.2.0]ヘプタン-6-イル、
イソインドリン-2-イル、及び
オクタヒドロシクロペンタ[c]ピロール-2-イル
から選択される6、7、8、9、又は10員の複素二環式基を形成し、
そのそれぞれが、C₁〜C₃アルキルからそれぞれ独立に選択される1つ又は2つの置換基で任意選択で置換されている、付記1から13のいずれか一つに記載の化合物又はその薬学的に許容される塩。
（付記４１）
(2S)-2-メチル-1-((R)-2-(3-メチル-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド)プロピル)ピロリジン-1-イウムホルメート;
N-(2-(3-アザビシクロ[3.2.1]オクタン-3-イル)エチル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(R)-N-(1-(イソインドリン-2-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
N-((2R)-1-(3-アザビシクロ[3.1.0]ヘキサン-3-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(S)-N-(1-シクロプロピル-2-(ピロリジン-1-イル)エチル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(R)-N-(1-シクロプロピル-2-(ピロリジン-1-イル)エチル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(R)-N-(1-(3,4-ジヒドロイソキノリン-2(1H)-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(R)-N-(1-(3-フェニルアゼチジン-1-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
D1: N-((R)-1-((abs)-3-(ジフルオロメトキシ)ピペリジン-1-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
D2: N-((R)-1-((abs)-3-(ジフルオロメトキシ)ピペリジン-1-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(R)-N-(1-(5-アザスピロ[2.5]オクタン-5-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(R)-N-(1-(6-アザスピロ[2.5]オクタン-6-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(R)-N-(1-(アゼパン-1-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(R)-N-(1-(1-アザスピロ[3.3]ヘプタン-1-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(R)-N-(1-(5-アザスピロ[2.4]ヘプタン-5-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
N-((R)-1-(3-アザビシクロ[3.2.1]オクタン-3-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
2-((R)-2-(4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド)プロピル)オクタヒドロシクロペンタ[c]ピロール-2-イウムホルメート;
(R)-N-(1-(3,4-ジヒドロ-2,7-ナフチリジン-2(1H)-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
N-((2R)-1-(3-アザビシクロ[3.2.0]ヘプタン-3-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
D1: N-((R)-1-((abs-1,5-cis)-6-アザビシクロ[3.2.0]ヘプタン-6-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
D2: N-((R)-1-((abs-1,5-cis)-6-アザビシクロ[3.2.0]ヘプタン-6-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
N-((2R)-1-(6,6-ジメチル-3-アザビシクロ[3.1.0]ヘキサン-3-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
(2S)-1-((R)-2-(3-フルオロ-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド)プロピル)-2-メチルピロリジン-1-イウムホルメート;
N-((R)-1-((S)-2-メチルピロリジン-1-イル)プロパン-2-イル)-5-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ピコリンアミド;
3-メチル-N-((R)-1-((S)-2-メチルピロリジン-1-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
N-((2R)-1-(ヘキサヒドロシクロペンタ[c]ピロール-2(1H)-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド;
3-フルオロ-N-((R)-1-((S)-2-メチルピロリジン-1-イル)プロパン-2-イル)-4-(5-(トリフルオロメチル)-1,2,4-オキサジアゾール-3-イル)ベンズアミド
又はその薬学的に許容される塩から選択される、付記1に記載の化合物又はその薬学的に許容される塩。
（付記４２）
付記1〜41のいずれか一つに記載の化合物又はその薬学的に許容される塩、及び薬学的に許容される担体を含む、医薬組成物。
（付記４３）
医薬組成物を製造する方法であって、付記1〜41のいずれか一つに記載の化合物又はその薬学的に許容される塩、及び薬学的に許容される担体を混合することを含む、前記方法。
（付記４４）
それを必要とする患者において、少なくとも1種のヒストンデアセチラーゼによって媒介される状態又は障害を治療する方法であって、前記患者へ、付記1〜41のいずれか一つに記載の治療有効量の化合物又はその薬学的に許容される塩を投与することを含む、前記方法。
（付記４５）
それを必要とする患者において、少なくとも1種のヒストンデアセチラーゼの阻害に反応性がある状態又は障害を治療する方法であって、前記患者へ、付記1〜41のいずれか一つに記載の治療有効量の化合物又はその薬学的に許容される塩を投与することを含む、方法。
（付記４６）
前記少なくとも1種のヒストンデアセチラーゼが、HDAC-4である、付記44又は45に記載の方法。
（付記４７）
前記状態又は障害が、神経変性の病態を含む、付記44又は45に記載の方法。
（付記４８）
前記状態又は障害が、ハンチントン病である、付記44又は45に記載の方法。 Although some embodiments are shown and described, various modifications and replacements may be made therein without departing from the spirit and scope of the present disclosure. For example, for the purposes of constructing the claims, the claims that are subsequently revealed are to be construed in any way that is narrower than their literal language, and thus the exemplary implementation from this specification. The form is not intended to be read into the claims. Therefore, it should be understood that the present disclosure is provided by way of illustration and there is no limitation on the scope of the claims.
(Additional note)
(Appendix 1)
Equation I

[During the ceremony,
W is N or CR ⁵ ; X is N or CR ⁶ ; Y is N or CR ⁷ ; Z is N or CR ⁸ ; where W, X, Y, and Z Two or less of them are N;
R ¹ is selected from H and C _{1 to} C ₃ alkyl;
R ² is C ₂ -C ₃ alkylene which is optionally substituted with C ₁ -C ₂ haloalkyl, or 3 or 4-membered cycloalkyl;
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
4, 5, 6, or 7-membered complex monocyclic group, or
Form 6, 7, 8, 9, or 10-membered complex bicyclic groups,
Each of them is C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, It is optionally substituted with 1 to 5 substituents independently selected from 3- or 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, where the aryl and heteroaryl are C ₁ Further optionally further substituted with 1 to 5 substituents independently selected from ~ C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively.
However, if R ³ and R ⁴ combine with the nitrogen atom to which they are attached to form a 5- or 6-membered complex monocyclic group.
i) R ² is a C ₂ -C ₃ alkylene substituted with C ₁ -C ₂ haloalkyl, or 3 or 4-membered cycloalkyl, or
ii) R ⁸ is halo or C _{1 to} C ₃ alkyl, or
iii) 5- or 6-membered heteromonocyclic groups are C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy. , 3 or 4 membered cycloalkyl, 3 or 4 membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, each substituted with 1-5 substituents independently selected, where aryl and Heteroaryls are optionally further substituted with 1 to 5 substituents, each independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo;
R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from H, C _{1 to} C ₄ alkyl, C _{1 to} C ₄ haloalkyl, and halo, respectively]
Or a pharmaceutically acceptable salt thereof, an optical isomer or a mixture of optical isomers thereof.
(Appendix 2)
A compound of formula I is a compound of formula II

The compound according to Appendix 1 or a pharmaceutically acceptable salt thereof, which is a compound of the above.
(Appendix 3)
The compound according to Appendix 1 or 2, or a pharmaceutically acceptable salt thereof, wherein R ² is a C _{2 to} C ₃ alkylene optionally substituted with a 3- or 4-membered cycloalkyl.
(Appendix 4)
The compound of formula I is formula III

The compound according to Appendix 3, or a pharmaceutically acceptable salt thereof, which is a compound of.
(Appendix 5)
The compound according to any one of Supplementary note 1 to 4, wherein R ⁶ is H, or a pharmaceutically acceptable salt thereof.
(Appendix 6)
The compound of formula I is formula V

The compound according to Appendix 1 or a pharmaceutically acceptable salt thereof, which is a compound of the above.
(Appendix 7)
The compound according to Appendix 6 or a pharmaceutically acceptable salt thereof, wherein R ² is a C _{2 to} C ₃ alkylene optionally substituted with a 3- or 4-membered cycloalkyl.
(Appendix 8)
The compound of formula I is the formula VI

The compound according to Appendix 7, or a pharmaceutically acceptable salt thereof.
(Appendix 9)
The compound according to any one of Supplementary notes 1 to 8 or a pharmaceutically acceptable salt thereof, wherein R ⁵ is H.
(Appendix 10)
The compound according to any one of Appendix 1 to 9, wherein R ⁷ is H, or a pharmaceutically acceptable salt thereof.
(Appendix 11)
The compound according to any one of Supplementary notes 1 to 10, wherein R ⁸ is selected from H, halo, and methyl, or a pharmaceutically acceptable salt thereof.
(Appendix 12)
The compound according to any one of Supplementary notes 1 to 11, wherein R ¹ is selected from H and methyl, or a pharmaceutically acceptable salt thereof.
(Appendix 13)
The compound according to Appendix 12 or a pharmaceutically acceptable salt thereof, wherein R ¹ is H.
(Appendix 14)
R ³ and R ⁴ together with the nitrogen atom to which they are attached, C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, With 1 to 5 substituents independently selected from 3- or 4-membered cycloalkoxy, 3- or 4-membered cycloalkyl, 3- or 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. Arbitrarily substituted 4- or 7-membered heteromonocyclic groups are formed, where aryls and heteroaryls are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. The compound according to any one of Supplementary notes 1 to 13, or a pharmaceutically acceptable salt thereof, which is further optionally further substituted with 1 to 5 substituents.
(Appendix 15)
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
The compound according to Appendix 14 or a pharmaceutically acceptable salt thereof, which forms a 4- or 7-membered complex monocyclic group selected from 3-phenylazetidine-1-yl and azepan-1-yl.
(Appendix 16)
R ³ and R ⁴ together with the nitrogen atom to which they are attached, C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, With 1 to 5 substituents independently selected from 3- or 4-membered cycloalkoxy, 3- or 4-membered cycloalkyl, 3- or 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. Arbitrarily substituted 5- or 6-membered heteromonocyclic groups are formed, where the aryls and heteroaryls are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. Is further optionally further substituted with 1-5 substituents,
The compound according to any one of Supplementary notes 1 to 13, wherein R ² is C _{1 to} C ₂ haloalkyl or C _{2 to} C ₃ alkylene substituted with 3 or 4 member cycloalkyl, or pharmaceutically thereof. Allowable salt.
(Appendix 17)
R ³ and R ⁴ together with the nitrogen atom to which they are attached, C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, Arbitrarily substituted with 1-5 substituents independently selected from 3- or 4-membered cycloalkoxy, 3- or 4-membered cycloalkyl, 3- or 4-membered heterocycloalkyl, aryl, and heteroaryl, respectively. Forming a 5- or 6-membered heteromonocyclic group, where aryls and heteroaryls are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively, 1 to 5 The compound according to Appendix 16 or a pharmaceutically acceptable salt thereof, which is further optionally further substituted with a substituent.
(Appendix 18)
₁ to 5 substitutions in which R ³ and R ⁴ are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and aryl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group optionally substituted with a group, where the aryl is independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. The compound according to Appendix 17, or a pharmaceutically acceptable salt thereof, which is further optionally further substituted with 1 to 5 substituents.
(Appendix 19)
₁ to 5 substitutions in which R ³ and R ⁴ are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and phenyl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group optionally substituted with a group, where phenyl is independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. The compound according to Appendix 18, or a pharmaceutically acceptable salt thereof, which is further optionally further substituted with 1 to 5 substituents.
(Appendix 20)
R ³ and R ⁴ are optionally substituted with 1 to 5 substituents, each independently selected from methyl, difluoromethoxy, and phenyl, together with the nitrogen atom to which they are attached5. Alternatively, the compound according to Appendix 19 or a pharmaceutically acceptable salt thereof, which forms a 6-membered heteromonocyclic group.
(Appendix 21)
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 5- or 6-membered heteromonocyclic group selected from pyrrolidine-1-yl and piperidine-1-yl. , Each of which is optionally substituted with one substituent selected from methyl, difluoromethoxy, and phenyl, according to Appendix 20, a pharmaceutically acceptable salt thereof.
(Appendix 22)
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
Pyrrolidine-1-yl,
2-Methyl-pyrrolidin-1-yl, and
The compound according to Appendix 21, or a pharmaceutically acceptable salt thereof, which forms a 5- or 6-membered complex monocyclic group selected from 3- (difluoromethoxy) piperidine-1-yl.
(Appendix 23)
R ³ and R ⁴ together with the nitrogen atom to which they are attached, C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, With 1 to 5 substituents independently selected from 3- or 4-membered cycloalkoxy, 3- or 4-membered cycloalkyl, 3- or 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. Arbitrarily substituted 5- or 6-membered heteromonocyclic groups are formed, where the aryls and heteroaryls are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. Is further optionally further substituted with 1-5 substituents,
The compound according to any one of Appendix 1 to 13 or a pharmaceutically acceptable salt thereof, wherein R ⁸ is halo or C _{1 to} C ₃ alkyl.
(Appendix 24)
R ³ and R ⁴ together with the nitrogen atom to which they are attached, C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, Arbitrarily substituted with 1-5 substituents independently selected from 3- or 4-membered cycloalkoxy, 3- or 4-membered cycloalkyl, 3- or 4-membered heterocycloalkyl, aryl, and heteroaryl, respectively. Forming a 5- or 6-membered heteromonocyclic group, where aryls and heteroaryls are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively, 1 to 5 The compound according to Appendix 23 or a pharmaceutically acceptable salt thereof, which is further optionally further substituted with a substituent.
(Appendix 25)
₁ to 5 substitutions in which R ³ and R ⁴ are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and aryl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group optionally substituted with a group, where the aryl is independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. The compound according to Appendix 24 or a pharmaceutically acceptable salt thereof, which is further optionally further substituted with 1 to 5 substituents.
(Appendix 26)
₁ to 5 substitutions in which R ³ and R ⁴ are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and phenyl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group optionally substituted with a group, where phenyl is independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. The compound according to Appendix 25 or a pharmaceutically acceptable salt thereof, which is further optionally further substituted with 1 to 5 substituents.
(Appendix 27)
R ³ and R ⁴ are optionally substituted with 1 to 5 substituents, each independently selected from methyl, difluoromethoxy, and phenyl, together with the nitrogen atom to which they are attached5. Alternatively, the compound according to Appendix 26 or a pharmaceutically acceptable salt thereof, which forms a 6-membered heteromonocyclic group.
(Appendix 28)
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 5- or 6-membered heteromonocyclic group selected from pyrrolidine-1-yl and piperidine-1-yl. , Each of which is optionally substituted with one substituent selected from methyl, difluoromethoxy, and phenyl, according to Appendix 27, or a pharmaceutically acceptable salt thereof.
(Appendix 29)
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
Pyrrolidine-1-yl,
2-Methyl-pyrrolidin-1-yl, and
The compound according to Appendix 28 or a pharmaceutically acceptable salt thereof, which forms a 5- or 6-membered complex monocyclic group selected from 3- (difluoromethoxy) piperidine-1-yl.
(Appendix 30)
R ³ and R ⁴ together with the nitrogen atom to which they are attached, C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, With 1 to 5 substituents independently selected from 3 or 4 membered cycloalkoxy, 3 or 4 membered cycloalkyl, 3 or 4 membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. It forms a substituted 5- or 6-membered heteromonocyclic group, where aryl and heteroaryl are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. The compound according to any one of Supplementary notes 1 to 13, or a pharmaceutically acceptable salt thereof, which is further optionally further substituted with 5 substituents.
(Appendix 31)
₁ to 5 substitutions in which R ³ and R ⁴ are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and aryl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group substituted with a group, where the aryl is independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. The compound according to Appendix 30, or a pharmaceutically acceptable salt thereof, which is further optionally further substituted with 5 substituents.
(Appendix 32)
₁ to 5 substitutions in which R ³ and R ⁴ are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and phenyl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group substituted with a group, where phenyl is independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. The compound according to Appendix 31, or a pharmaceutically acceptable salt thereof, which is further optionally further substituted with 5 substituents.
(Appendix 33)
5 or 6 members in which R ³ and R ⁴ are substituted with 1 to 5 substituents independently selected from methyl, difluoromethoxy, and phenyl, together with the nitrogen atom to which they are attached. The compound according to Appendix 32 or a pharmaceutically acceptable salt thereof, which forms a heteromonocyclic group of.
(Appendix 34)
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 5- or 6-membered heteromonocyclic group selected from pyrrolidine-1-yl and piperidine-1-yl. , Each of which is substituted with one substituent selected from methyl, difluoromethoxy, and phenyl, according to Appendix 33, or a pharmaceutically acceptable salt thereof.
(Appendix 35)
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
2-Methyl-pyrrolidin-1-yl, and
The compound according to Appendix 34 or a pharmaceutically acceptable salt thereof, which forms a 5- or 6-membered complex monocyclic group selected from 3- (difluoromethoxy) piperidine-1-yl.
(Appendix 36)
The compound according to any one of Supplementary note 1 to 13, wherein R ³ and R ⁴ form (2S) -methyl-pyrrolidin-1-yl together with the nitrogen atom to which they are bonded. Its pharmaceutically acceptable salt.
(Appendix 37)
R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 6, 7, 8, 9, or 10-membered heterobicyclic group, which is C. _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 or 4 member hetero It is optionally substituted with 1 to 5 substituents independently selected from cycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, where aryl and heteroaryl are C _{1 to} C ₃ alkyl, C. The compound according to any one of Supplementary notes 1 to 13, which is further optionally further substituted with 1 to 5 substituents independently selected from _{1 to} C ₃ haloalkyl and halo, or pharmaceutically acceptable thereof. Salt to be done.
(Appendix 38)
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
1-Azaspiracid [3.3] Heptane-1-yl,
3-Azabicyclo [3.1.0] Hexane-3-yl,
3-Azabicyclo [3.2.0] Heptane-3-yl,
3-Azabicyclo [3.2.1] Heptane-3-yl,
3-Azabicyclo [3.2.1] Octane-3-yl,
3,4-dihydroisoquinoline-2 (1H) -yl,
3,4-Dihydro-2,7-Diazanaphthalene-2 (1H) -Il,
5-Azaspiracid [2.4] Heptane-5-Il,
5-Azaspiracid [2.5] Octane-5-Il,
6-Azaspiracid [2.5] Octane-6-Il,
1-Azaspiracid [3.3] Heptane-1-yl,
6-Azabicyclo [3.2.0] Heptane-6-Il,
Forming 6, 7, 8, 9, or 10-membered complex bicyclic groups selected from isoindoline-2-yl and octahydrocyclopenta [c] pyrrole-2-yl,
Each of them is C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 Alternatively, they are optionally substituted with 1 to 5 substituents independently selected from the 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, wherein the aryl and heteroaryl are C ₁ to. The compound according to any one of Appendix 1 to 13, further optionally further substituted with 1 to 5 substituents independently selected from C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. Its pharmaceutically acceptable salt.
(Appendix 39)
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
1-Azaspiracid [3.3] Heptane-1-yl,
3-Azabicyclo [3.1.0] Hexane-3-yl,
3-Azabicyclo [3.2.0] Heptane-3-yl,
3-Azabicyclo [3.2.1] Heptane-3-yl,
3-Azabicyclo [3.2.1] Octane-3-yl,
3,4-dihydroisoquinoline-2 (1H) -yl,
3,4-Dihydro-2,7-Diazanaphthalene-2 (1H) -Il,
5-Azaspiracid [2.4] Heptane-5-Il,
5-Azaspiracid [2.5] Octane-5-Il,
6-Azaspiracid [2.5] Octane-6-Il,
1-Azaspiracid [3.3] Heptane-1-yl,
6-Azabicyclo [3.2.0] Heptane-6-Il,
Forming 6, 7, 8, 9, or 10-membered complex bicyclic groups selected from isoindoline-2-yl and octahydrocyclopenta [c] pyrrole-2-yl,
Each of them is one or two substituents independently selected from C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, and carboxy, respectively. The compound according to any one of Appendix 1 to 13 or a pharmaceutically acceptable salt thereof, which is optionally substituted.
(Appendix 40)
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
1-Azaspiracid [3.3] Heptane-1-yl,
3-Azabicyclo [3.1.0] Hexane-3-yl,
3-Azabicyclo [3.2.0] Heptane-3-yl,
3-Azabicyclo [3.2.1] Heptane-3-yl,
3-Azabicyclo [3.2.1] Octane-3-yl,
3,4-dihydroisoquinoline-2 (1H) -yl,
3,4-Dihydro-2,7-Diazanaphthalene-2 (1H) -Il,
5-Azaspiracid [2.4] Heptane-5-Il,
5-Azaspiracid [2.5] Octane-5-Il,
6-Azaspiracid [2.5] Octane-6-Il,
1-Azaspiracid [3.3] Heptane-1-yl,
6-Azabicyclo [3.2.0] Heptane-6-Il,
Forming 6, 7, 8, 9, or 10-membered complex bicyclic groups selected from isoindoline-2-yl and octahydrocyclopenta [c] pyrrole-2-yl,
The compound according to any one of Supplementary notes 1 to 13, wherein each of which is optionally substituted with one or two substituents independently selected from the C _{1 to} C ₃ alkyl, or pharmaceuticals thereof. Tolerant salt.
(Appendix 41)
(2S) -2-Methyl-1-((R) -2-(3-Methyl-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl ) Pyrrolidine-1-iumformate;
N-(2- (3-azabicyclo [3.2.1] octane-3-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
(R) -N- (1- (isoindoline-2-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide ;
N-((2R) -1- (3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
(S) -N- (1-Cyclopropyl-2- (pyrrolidin-1-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide ;
(R) -N- (1-Cyclopropyl-2- (pyrrolidin-1-yl) ethyl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide ;
(R) -N- (1- (3,4-dihydroisoquinoline-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
(R) -N- (1- (3-Phenylazetidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3- Il) Benzamide;
D1: N-((R) -1-((abs) -3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2, 4-Oxadiazole-3-yl) benzamide;
D2: N-((R) -1-((abs) -3- (difluoromethoxy) piperidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2, 4-Oxadiazole-3-yl) benzamide;
(R) -N- (1- (5-azaspiro [2.5] octane-5-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
(R) -N- (1- (6-azaspiro [2.5] octane-6-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
(R) -N- (1- (azepan-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
(R) -N- (1- (1-azaspiro [3.3] heptane-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
(R) -N- (1- (5-azaspiro [2.4] heptane-5-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadiazole- 3-Il) Benzamide;
N-((R) -1- (3-azabicyclo [3.2.1] octane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
2-((R) -2-(4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl) octahydrocyclopenta [c] pyrrole-2- Iumformate;
(R) -N- (1- (3,4-dihydro-2,7-naphthylidine-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2 , 4-Oxadiazole-3-yl) benzamide;
N-((2R) -1- (3-azabicyclo [3.2.0] heptane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4-oxadi Azole-3-yl) benzamide;
D1: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl) propan-2-yl) -4- (5- (tri) Fluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
D2: N-((R) -1-((abs-1,5-cis) -6-azabicyclo [3.2.0] heptane-6-yl) propan-2-yl) -4- (5- (tri) Fluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide;
N-((2R) -1- (6,6-dimethyl-3-azabicyclo [3.1.0] hexane-3-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1, 2,4-Oxadiazole-3-yl) benzamide;
(2S) -1-((R) -2- (3-Fluoro-4- (5- (trifluoromethyl) -1,2,4-oxadiazole-3-yl) benzamide) propyl) -2- Methylpyrrolidine-1-iamformate;
N-((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) -5- (5- (trifluoromethyl) -1,2,4-oxadiazole -3-Il) Picoline amide;
3-Methyl-N-((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4 -Oxadiazole-3-yl) benzamide;
N-((2R) -1- (hexahydrocyclopenta [c] pyrrole-2 (1H) -yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4- Oxadiazole-3-yl) benzamide;
3-Fluoro-N-((R) -1-((S) -2-methylpyrrolidine-1-yl) propan-2-yl) -4- (5- (trifluoromethyl) -1,2,4 -Oxadiazole-3-yl) The compound according to Appendix 1 or a pharmaceutically acceptable salt thereof, which is selected from benzamide or a pharmaceutically acceptable salt thereof.
(Appendix 42)
A pharmaceutical composition comprising the compound according to any one of Supplementary notes 1 to 41 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
(Appendix 43)
A method for producing a pharmaceutical composition, which comprises mixing the compound according to any one of Supplementary notes 1 to 41 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. Method.
(Appendix 44)
A method for treating a condition or disorder mediated by at least one histone deacetylase in a patient in need thereof, the therapeutically effective amount according to any one of Supplementary note 1 to 41 to the patient. The method comprising administering a compound of, or a pharmaceutically acceptable salt thereof.
(Appendix 45)
A method for treating a condition or disorder that is responsive to inhibition of at least one histone deacetylase in a patient in need thereof, as described in any one of Supplementary notes 1-41 to the patient. A method comprising administering a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof.
(Appendix 46)
The method according to Appendix 44 or 45, wherein the at least one histone deacetylase is HDAC-4.
(Appendix 47)
44. The method of Appendix 44 or 45, wherein the condition or disorder comprises a pathological condition of neurodegeneration.
(Appendix 48)
The method according to Appendix 44 or 45, wherein the condition or disorder is Huntington's disease.

Claims (35)

Equation I

[During the ceremony,
W is N or CR ⁵ ; X is N or CR ⁶ ; Y is N or CR ⁷ ; Z is N or CR ⁸ ; where W, X, Y, and Z Two or less of them are N;
R ¹ is selected from H and C _{1 to} C ₃ alkyl;
R ² is C ₂ -C ₃ alkylene which is optionally substituted with C ₁ -C ₂ haloalkyl, or 3 or 4-membered cycloalkyl;
R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 or 4 member A 4- or 7-membered heteromonocyclic group optionally substituted with 1 to 5 substituents independently selected from heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. Aryls and heteroaryls are here optionally further substituted with 1 to 5 substituents independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively, 4 or 7 Member heteromonocyclic group, or
C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 or 4 member A 5- or 6-membered heteromonocyclic group optionally substituted with 1 to 5 substituents independently selected from heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. Here, aryl and heteroaryl are further optionally further substituted with 1 to 5 substituents independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively, 5 or 6 Member heteromonocyclic group, or
1-Azaspiracid [3.3] Heptane-1-yl,
3-Azabicyclo [3.1.0] Hexane-3-yl,
3-Azabicyclo [3.2.0] Heptane-3-yl,
3-Azabicyclo [3.2.1] Heptane-3-yl,
3-Azabicyclo [3.2.1] Octane-3-yl,
3,4-dihydroisoquinoline-2 (1H) -yl,
3,4-Dihydro-2,7-Diazanaphthalene-2 (1H) -Il,
5-Azaspiracid [2.4] Heptane-5-Il,
5-Azaspiracid [2.5] Octane-5-Il,
6-Azaspiracid [2.5] Octane-6-Il,
1-Azaspiracid [3.3] Heptane-1-yl,
6-Azabicyclo [3.2.0] Heptane-6-Il,
A 6,7,8,9, or 10-membered heterobicyclic group selected from isoindrin-2-yl and octahydrocyclopenta [c] pyrrol-2-yl, each of which contains C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 or 4 member Heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl are optionally substituted with 1 to 5 substituents, respectively, where aryl and heteroaryl are C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyls, and 6, 7, 8, 9, or 10-membered heterobicyclic groups optionally further substituted with 1 to 5 substituents independently selected from halos. formed,
R ⁵ , R ⁶ , R ⁷ and R ⁸ are independently selected from H, C _{1 to} C ₄ alkyl, C _{1 to} C ₄ haloalkyl, and halo, respectively .
However, if R ³ and R ⁴ combine with the nitrogen atom to which they are bonded to form a 5- or 6-membered complex monocyclic group.
R ² is C ₂ -C ₃ alkylene substituted with C ₁ -C ₂ haloalkyl, or 3 or 4-membered cycloalkyl]
Or a pharmaceutically acceptable salt thereof, an optical isomer or a mixture of optical isomers thereof. A compound of formula I is a compound of formula II

The compound according to claim 1 or a pharmaceutically acceptable salt, optical isomer, or mixture of optical isomers thereof. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt or optical isomer thereof, wherein R ² is a C _{2 to} C ₃ alkylene optionally substituted with a 3- or 4-membered cycloalkyl. Or a mixture of optical isomers. The compound of formula I is formula III

The compound according to claim 3 or a pharmaceutically acceptable salt, optical isomer or mixture of optical isomers thereof. The compound according to any one of claims 1 to 4, wherein R ⁶ is H, or a pharmaceutically acceptable salt, optical isomer or mixture of optical isomers thereof. The compound of formula I is formula V

The compound according to claim 1 or a pharmaceutically acceptable salt, optical isomer, or mixture of optical isomers thereof. The compound of claim 6 or a pharmaceutically acceptable salt, optical isomer or optical thereof, wherein R ² is a C _{2 to} C ₃ alkylene optionally substituted with a 3- or 4-membered cycloalkyl. A mixture of isomers. The compound of formula I is the formula VI

7. The compound according to claim 7 or a pharmaceutically acceptable salt, optical isomer or mixture of optical isomers thereof. The compound according to any one of claims 1 to 8, wherein R ⁵ is H, or a pharmaceutically acceptable salt, optical isomer or mixture of optical isomers thereof. The compound according to any one of claims 1 to 9, wherein R ⁷ is H, or a pharmaceutically acceptable salt, optical isomer or mixture of optical isomers thereof. The compound according to any one of claims 1 to 10, wherein R ⁸ is selected from H, halo, and methyl, or a pharmaceutically acceptable salt, optical isomer, or mixture of optical isomers thereof. The compound according to any one of claims 1 to 11, wherein R ¹ is selected from H and methyl, or a pharmaceutically acceptable salt, optical isomer or mixture thereof. The compound according to claim 12, wherein R ¹ is H, or a pharmaceutically acceptable salt, optical isomer, or mixture of optical isomers thereof. R ³ and R ⁴ together with the nitrogen atom to which they are attached, C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, With 1 to 5 substituents independently selected from 3 or 4 membered cycloalkoxy, 3 or 4 membered cycloalkyl, 3 or 4 membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. Arbitrarily substituted 4- or 7-membered heteromonocyclic groups are formed, where the aryl and heteroaryl are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. Of the compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt, optical isomer or optical isomer thereof, which is further optionally further substituted with 1 to 5 substituents. blend. R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
The compound according to claim 14, or a pharmaceutically acceptable salt thereof, which forms a 4- or 7-membered heteromonocyclic group selected from 3-phenylazetidine-1-yl and azepan-1-yl. , Optical isomers or mixtures of optical isomers. R ³ and R ⁴ together with the nitrogen atom to which they are attached, C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, With 1 to 5 substituents independently selected from 3- or 4-membered cycloalkoxy, 3- or 4-membered cycloalkyl, 3- or 4-membered heterocycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, respectively. Arbitrarily substituted 5- or 6-membered heteromonocyclic groups are formed, where the aryls and heteroaryls are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. Is further optionally further substituted with 1-5 substituents,
The compound according to any one of claims 1 to 13, wherein R ² is a C _{1 to} C ₂ haloalkyl or a C _{2 to} C ₃ alkylene substituted with a 3 or 4 member cycloalkyl, or a pharmaceutically thereof. An acceptable salt, optical isomer or mixture of optical isomers. R ³ and R ⁴ together with the nitrogen atom to which they are attached, C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, Arbitrarily substituted with 1-5 substituents independently selected from 3- or 4-membered cycloalkoxy, 3- or 4-membered cycloalkyl, 3- or 4-membered heterocycloalkyl, aryl, and heteroaryl, respectively. Forming a 5- or 6-membered heteromonocyclic group, where aryls and heteroaryls are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively, 1 to 5 The compound according to claim 16 or a pharmaceutically acceptable salt, optical isomer or mixture of optical isomers thereof, which is further optionally further substituted with a substituent. ₁ to 5 substitutions in which R ³ and R ⁴ are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and aryl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group optionally substituted with a group, where the aryl is independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. The compound according to claim 17, or a pharmaceutically acceptable salt, optical isomer or mixture of optical isomers thereof, which is further optionally further substituted with 1 to 5 substituents. ₁ to 5 substitutions in which R ³ and R ⁴ are independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, and phenyl, respectively, together with the nitrogen atom to which they are attached. It forms a 5- or 6-membered heteromonocyclic group optionally substituted with a group, where phenyl is independently selected from C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkyl, and halo, respectively. The compound according to claim 18, or a pharmaceutically acceptable salt, optical isomer or mixture of optical isomers thereof, which is further optionally further substituted with 1 to 5 substituents. R ³ and R ⁴ are optionally substituted with 1 to 5 substituents, each independently selected from methyl, difluoromethoxy, and phenyl, together with the nitrogen atom to which they are attached5. Or the compound according to claim 19 or a pharmaceutically acceptable salt, optical isomer or mixture of optical isomers thereof, which forms a 6-membered heteromonocyclic group. R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 5- or 6-membered heteromonocyclic group selected from pyrrolidine-1-yl and piperidine-1-yl. , Each of which is optionally substituted with one substituent selected from methyl, difluoromethoxy, and phenyl, the compound according to claim 20, or a pharmaceutically acceptable salt, optical isomer thereof, or A mixture of optical isomers. R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
Pyrrolidine-1-yl,
2-Methyl-pyrrolidin-1-yl, and
The compound according to claim 21 or a pharmaceutically acceptable salt, optical isomer or pharmaceutically acceptable salt thereof, which forms a 5- or 6-membered heteromonocyclic group selected from 3- (difluoromethoxy) piperidine-1-yl. A mixture of optical isomers.
The compound of claim 1 or pharmaceutically acceptable thereof, wherein R ³ and R ⁴ together with the nitrogen atom to which they are attached form (2S) -methyl-pyrrolidin-1-yl. Salt, optical isomer or mixture of optical isomers. R ³ and R ⁴ together with the nitrogen atom to which they are attached form a 6, 7, 8, 9, or 10-membered heterobicyclic group, which is C. _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, 3 or 4 member cycloalkoxy, 3 or 4 member cycloalkyl, 3 or 4 member hetero It is optionally substituted with 1 to 5 substituents independently selected from cycloalkyl, carboxy, aryl, cyano, halo, and heteroaryl, where aryl and heteroaryl are C _{1 to} C ₃ alkyl, C. The compound according to any one of claims 1 to 13, which is further optionally further substituted with 1 to 5 substituents independently selected from _{1 to} C ₃ haloalkyl, and halo, respectively, or pharmaceutically thereof. Acceptable salts, optical isomers or mixtures of optical isomers. R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
1-Azaspiracid [3.3] Heptane-1-yl,
3-Azabicyclo [3.1.0] Hexane-3-yl,
3-Azabicyclo [3.2.0] Heptane-3-yl,
3-Azabicyclo [3.2.1] Heptane-3-yl,
3-Azabicyclo [3.2.1] Octane-3-yl,
3,4-dihydroisoquinoline-2 (1H) -yl,
3,4-Dihydro-2,7-Diazanaphthalene-2 (1H) -Il,
5-Azaspiracid [2.4] Heptane-5-Il,
5-Azaspiracid [2.5] Octane-5-Il,
6-Azaspiracid [2.5] Octane-6-Il,
1-Azaspiracid [3.3] Heptane-1-yl,
6-Azabicyclo [3.2.0] Heptane-6-Il,
Forming 6, 7, 8, 9, or 10-membered complex bicyclic groups selected from isoindoline-2-yl and octahydrocyclopenta [c] pyrrole-2-yl,
Each of them is one or two substituents independently selected from C _{1 to} C ₃ alkoxy, C _{1 to} C ₃ alkyl, C _{1 to} C ₃ haloalkoxy, C _{1 to} C ₃ haloalkyl, and carboxy, respectively. The compound according to any one of claims 1 to 13, which is optionally substituted, or a pharmaceutically acceptable salt, optical isomer or mixture of optical isomers thereof. R ³ and R ⁴ together with the nitrogen atom to which they are bonded,
1-Azaspiracid [3.3] Heptane-1-yl,
3-Azabicyclo [3.1.0] Hexane-3-yl,
3-Azabicyclo [3.2.0] Heptane-3-yl,
3-Azabicyclo [3.2.1] Heptane-3-yl,
3-Azabicyclo [3.2.1] Octane-3-yl,
3,4-dihydroisoquinoline-2 (1H) -yl,
3,4-Dihydro-2,7-Diazanaphthalene-2 (1H) -Il,
5-Azaspiracid [2.4] Heptane-5-Il,
5-Azaspiracid [2.5] Octane-5-Il,
6-Azaspiracid [2.5] Octane-6-Il,
1-Azaspiracid [3.3] Heptane-1-yl,
6-Azabicyclo [3.2.0] Heptane-6-Il,
Forming 6, 7, 8, 9, or 10-membered complex bicyclic groups selected from isoindoline-2-yl and octahydrocyclopenta [c] pyrrole-2-yl,
The compound according to any one of claims 1 to 13, wherein each of which is optionally substituted with one or two substituents independently selected from the C _{1 to} C ₃ alkyl, or pharmaceuticals thereof. Tolerable salts, optical isomers or mixtures of optical isomers. formula

Or an optical isomer thereof, a mixture of optical isomers thereof, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, an optical isomer or a mixture of optical isomers, and a pharmaceutically acceptable carrier. A method for producing a pharmaceutical composition, wherein the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof, an optical isomer or a mixture of optical isomers thereof, and a pharmaceutically acceptable mixture thereof. The method comprising mixing the carriers to be made. A pharmaceutical composition for treating a condition or disorder mediated by at least one histone deacetylase, wherein the pharmaceutical composition according to any one of claims 1 to 27 therapeutically effective amount of A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof, an optical isomer or a mixture of optical isomers thereof. A pharmaceutical composition for treating a condition or disorder is responsive to inhibition of at least one histone deacetylase, wherein the pharmaceutical composition comprises a therapeutically effective amount of any one of claims 1 to 27 A pharmaceutical composition comprising the compound described in 1 or a pharmaceutically acceptable salt thereof, an optical isomer or a mixture of optical isomers thereof. The pharmaceutical composition according to claim 30 or 31 , wherein the at least one histone deacetylase is HDAC-4. The pharmaceutical composition according to claim 30 or 31 , wherein the condition or disorder comprises a pathological condition of neurodegeneration. The pharmaceutical composition according to claim 30 or 31 , wherein the condition or disorder is Huntington's disease. A pharmaceutical composition for treating Huntington's disease, wherein the pharmaceutical composition is a therapeutically effective amount of the compound according to any one of claims 1 to 27, a pharmaceutically acceptable salt thereof, or an optical isomer. A pharmaceutical composition comprising a mixture of isomers or optical isomers.